Novel metallotexaphyrin derivatives

ABSTRACT

Novel derivatives of metallotexaphyrins are prepared by modifying the apical ligands associated with the central metal component of a metallotexaphyrin.

FIELD OF THE INVENTION

[0001] The present invention relates to methods for modifyingmetallotexaphyrins to provide metallotexaphyrin derivatives (MTDs)having a wide range of physicochemical properties. In particular, themethods involve modifying the apical ligands associated with the centralmetal component of metallotexaphyrins. The invention also relates to thenovel MTDs prepared by these methods, and their uses, and pharmaceuticalcompositions containing such compounds.

BACKGROUND INFORMATION

[0002] Porphyrins, the so-called “expanded porphyrins”, and relatedpolypyrrole structures are members of a class of macrocycles capable offorming stable complexes with metals. The metal is constrained (as itscation) within a central binding cavity of the macrocycle (the “core”).The anions associated with the metal cation are found above and belowthe core; and are called apical ligands. Examples of this class ofmacrocycles are porphyrins, porphyrin isomers, porphyrin-likemacrocycles, benzoporphyrins, texaphyrins, alaskaphyrins, sapphyrins,rubyrins, porphycenes, chlorins, benzochlorins, and purpurins.

[0003] One preferred class of macrocycles is the texaphyrins.Texaphyrins are aromatic pentadentate macrocyclic compounds that havethe ability to integrate metals within their core to form complexesknown as “metallotexaphyrins”. Texaphyrins and metallotexaphyrins havebeen described as being useful as MRI contrast agents, fluorescentimaging agents for cancer, plaque, and retinal diseases, asradiosensitizers and as chemosensitizers in both oncology andatherosclerosis, and as photosensitizers in photodynamic therapy inoncology, atherosclerosis, and ophthamology. They have also beendescribed as having the ability to hydrolytically cleave phosphateesters such as RNA, and to photolytically cleave RNA and DNA.Texaphyrins are aromatic benzannulene compounds containing both 18π- and227π-electron delocalization pathways. Texaphyrin molecules absorb lightstrongly in the tissue-transparent 700-900 nm range, and they exhibitselective uptake (or biolocalization) in certain tissues, particularlyregions such as liver, atheroma or tumor tissue, and neovascularizedregions. Such selectivity can be detected by magnetic resonance imaging(for example with paramagnetic metal complexes) and by fluorescence.

[0004] Accordingly, advantage may be taken of this property to provide ameans for selectively treating tumors, plaque caused by atherosclerosis,retinal diseases, and the like, as disclosed in the publicationsincorporated by reference below in the detailed description of theinvention. Notwithstanding these properties, it has remained desired toprovide new MTDs having a range of physicochemical properties, such, asimproved solubility and/or lipophilicity, lower toxicity, and improvedstability, but still retaining the basic attribute of selectivelocalization.

[0005] One method of accomplishing these goals would be to change theproperties of existing metallotexaphyrins by modifying the functionalgroups covalently attached to the macrocycle, and/or by changing thecore metal. However, preparations of such MTDs require complicatedsyntheses, since each compound is necessarily made by a differentsynthetic route, and/or is derived from different starting materials.Accordingly, there remains a need for a convenient method for preparinga library of texaphyrin derivatives, which vary in their physicochemicalproperties, and can be synthesized easily and efficiently in high yield.The present invention provides such a method by modifying the apicalligands associated with the metal component of existingmetallotexaphyrins to provide a library of MTDs having a wide range ofphysicochemical properties.

SUMMARY OF THE INVENTION

[0006] It is an object of this invention to provide novelmetallotexaphyrin derivatives (MTDs). Accordingly, in a first aspect,the invention relates to compounds having the Formula I:

[0007] wherein:

[0008] M is a metal cation;

[0009] AL is an apical ligand;

[0010] with the proviso that AL is not derived from acetic acid, nitricacid, or hydrochloric acid; n is an integer of 1-5;

[0011] R¹, R², R³, R⁴, R⁵, R⁶, R⁸, and R⁹ are independently chosen fromthe group consisting of hydrogen, halogen, hydroxyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, nitro, acyl, optionally substituted alkoxy, alkylalkoxy,saccharide, optionally substituted amino, carboxyl, optionallysubstituted carboxyalkyl, optionally substituted carboxyamide,optionally substituted carboxyamidealkyl, optionally substitutedheterocycle, optionally substituted cycloalkyl, optionally substitutedarylalkyl, optionally substituted heteroarylalkyl, optionallysubstituted heterocycloalkylalkyl; and a group -X-Y, in which X is acovalent bond or a linker and Y is a catalytic group, a chemotherapeuticagent, or a site-directing molecule, and;

[0012] R⁵, R¹⁰, R¹¹, and R¹² are independently hydrogen, optionallysubstituted alkyl, optionally substituted aryl, optionally substitutedalkoxy, optionally substituted carboxyalkyl, or optionally substitutedcarboxyamidealkyl; with the proviso that: halogen is other than iodideand haloalkyl is other than iodoalkyl.

[0013] Substituents R¹-R¹² are further described in U.S. patents, PCTpublications and allowed and pending patent applications, incorporatedby reference in the Detailed Description.

[0014] M can be monovalent, divalent, trivalent, or tetravalent.Examples of monovalent metal cations are tellurium and technetium; anexample of an appropriate tetravalent metal is thorium. Preferred aredivalent and trivalent metals. Preferred divalent metal cations areCa(II), Mn(II), Co(II), Ni(II), Zn(II), Cd(II), Hg(III), Fe(II), Sm(II),or U(II). Preferred trivalent metal cations are Mn(III), Co(III),Ni(III), Fe(III), Ho(III), Ce(III), Y(III), In(III), Pr(III), Nd(III),Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Er(III), Tm(III), Yb(III),Lu(III), La(III), or U(III). More preferred trivalent metal cations areLu(III) or Gd(III). In some embodiments, in particular for use inneutron capture therapy, the metal can be present as a pure isotope ofthe metal, or be enriched in one or more of its isotopes. For example,gadolinium may be present as its ¹⁵⁵Gd or ¹⁵⁷Gd isotope, or “natural”gadolinium may be optionally enriched in the isotopes ¹⁵⁵Gd and/or¹⁵⁷Gd. Similarly, cadmium may be present as the cadmium isotope ¹¹³Cd,or “natural” cadmium enriched in ¹¹³Cd; europium may be present as theeuropium isotope ¹¹⁵Eu, or “natural” europium enriched in ¹⁵¹Eu; mercurymay be present as the mercury isotope ¹⁹⁹Hg, or “natural” mercuryenriched in ¹⁹⁹Hg; and samarium may be present as the samarium isotope¹⁴⁹Sm. or “natural” samarium enriched in ¹⁴⁹Sm. Particularly preferredfor neutron capture therapy is the ¹⁵⁷Gd isotope of gadolinium, or“natural” gadolinium enriched in the isotope ¹⁵⁷Gd.

[0015] M or one of groups R¹ to R¹² can be radioactive, and are asdescribed in the U.S. patents, PCT publications, and allowed and pendingpatent applications disclosed and incorporated by reference below.

[0016] Preferred apical ligands are formed, for example, fromcarboxylates of sugar derivatives, such as gluconic acid or glucoronicacid, cholesterol derivatives such as cholic acid and deoxycholic acid,polyethylene glycol (PEG) acids, or carboxylic acid derivatives, such asformic acid, propionic acid, butyric acid, pentanoic acid, methylvalericacid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonicacid, succinic acid, maleic acid, fumaric acid, tartaric acid,3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic 2,5-dioxoheptanoic acid,citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid.Other preferred acids for forming apical ligands include methanesulfonicacid, ethanesulfonic acid, p-toluene-sulfonic acid, organophosphates,such as methylphosphonic acid and phenylphosphonic acid, phosphoric acidand the like.

[0017] A second aspect of the present invention relates to a preferredprocess for synthesizing MTDs of Formula I, comprising the steps ofcontacting the desired apical ligand with an quartenary amine resin(e.g., Ambersep 900(OH), Amberlite IRA904), contacting the apicalligand/amino acid resin complex thus produced with a metallotexaphyrin,preferably a metallotexaphyrin acetate, and isolating the MTD of FormulaI having the desired novel apical ligand.

[0018] A third aspect of the present invention relates to an alternativeprocess for synthesizing MTDs of Formula I, comprising the steps ofcontacting a metallotexaphyrin, preferably as an acetate, with a largeexcess of the chosen apical ligand, optionally heating the mixture, andisolating the MTD of Formula I containing the novel apical ligand.

[0019] A fourth aspect of the present invention relates to a process forsynthesizing MTDs having a mixture of apical ligands, comprising thesteps of contacting a metallotexaphyrin, preferably a metallotexaphyrinacetate, with a mixture of apical ligands, optionally heating themixture, and isolating the MTD of Formula I containing a mixture ofapical ligands. Alternatively, the reaction can be carried out in abiphasic fashion (for example, in a methylene chloride/water mixture).

[0020] A fifth aspect of this invention relates to pharmaceuticalformulations, comprising a therapeutically effective amount of an MTD ofFormula I and at least one pharmaceutically acceptable excipient.

[0021] A sixth aspect of this invention relates to a method of using theMTDs of Formula I in the treatment of a disease or condition in a mammalthat results from the presence of neoplastic tissue, which methodcomprises administering to a such a mammal a therapeutically effectiveamount of an MTD of Formula I, and optionally treating further with achemotherapeutic compound, or preferably treating the area in proximityto the neoplastic tissue with a therapeutic energy means. Preferredtherapeutic energies include photoirradiation, ionizing radiation,ultrasound, and neutron bombardment.

[0022] A seventh aspect of this invention relates to a method of usingthe MTDs of Formula I in the treatment of a disease or condition in amammal that results from the presence of atherosclerosis, which methodcomprises administering to a such a mammal a therapeutically effectiveamount of an MTD of Formula I, and treating the area in proximity to theplaque caused by atherosclerosis with a therapeutic energy means.Preferred therapeutic energies include photoirradiation, ionizingradiation, ultrasound, and neutron bombardment.

[0023] An eighth aspect of this invention relates to a method of usingthe MTDs of Formula I in the treatment of a disease or condition in amammal that results from areas of neovascularization, in particularage-related ocular degeneration, which method comprises administering toa such a mammal a therapeutically effective amount of an MTD of FormulaI, and treating the area in proximity to the neovascularization with atherapeutic energy means. Preferred therapeutic energies includephotoirradiation, ionizing radiation, ultrasound, and neutronbombardment.

DETAILED DESCRIPTION OF THE INVENTION

[0024] This invention provides novel metallotexaphyrin derivatives(MTDs) having a wide range of physicochemical and biological properties,and methods of making them. In particular, the invention provides amethod of exchanging the existing apical ligands of a metallotexaphyrinwith one or more different apical ligands. The apical ligand exchangemodifies the properties of the metallotexaphyrin by altering, forexample, its solubility, solution pH, partition coefficient, or otherphysicochemical properties. Changing the pharmacokinetics and/or thebiodistribution of the complex in this fashion may result in, forexample, better clearance and/or selective uptake in various tissues,such as tumor tissue, or atheromatous plaque.

[0025] For example, greater solubility of the MTD when placed in aphysiologically compatible buffer can be expected to give greater serumconcentration that can be obtained in vivo. This is useful, for example,in delivering the MTD directly to the area of plaque by intra-arterialinjection, in which case higher uptake can be achieved. Additionally,higher solubility leads to lower aggregation effects, which provideslower in-vivo toxicity.

[0026] In particular, gluconate or glucoronate apical ligands render theMTDs very soluble, and are consequently useful for indications that callfor higher plasma concentrations of the MTD. The higher solubility ofsuch compounds, as noted above, provides greater potential for tumoruptake of the compounds of the invention. Alternatively, cholate ordeoxycholate ligands decrease the compound's solubility and imparthydrophobicity. Hydrophobic compounds, when enclosed in a lipid vacuole,are useful for alternative delivery routes such as oral and topicaladministration. Additionally, by changing to amphiphilic apical ligandssuch as PEG acids, the MTDs of the invention can be made soluble in awide variety of solvents.

[0027] The existing apical ligands of a metallotexaphyrin can beexchanged for a wide range of different apical ligands, including monoor polyanionic ligands, such as carboxylates of sugar derivatives andcholesterol derivatives, PEG acids, organic acids, organosulfates,organophosphates, or phosphates or other inorganic ligands.

[0028] It should be noted that metallomacrocycles other thanmetallotexaphyrins can be modified in the same manner as summarizedabove. That is, metallomacrocycle derivatives can be prepared frommetallomacrocycles in a manner similar to those disclosed herein.Examples of macrocycles from which metallomacrocyclee derivative can bemade are porphyrins, porphyrin isomers, porphyrin-like macrocycles,benzoporphyrins , alaskaphyrins, sapphyrins, rubyrins, porphycenes,chlorins, benzochlorins, and purpurins.

Definitions and General Parameters

[0029] As used in the present specification, the following words andphrases are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

[0030] The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain preferably having from 1 to 20 carbon atoms,more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6carbon atoms. This term is exemplified by groups such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl,and the like.

[0031] The term “substituted alkyl” refers to

[0032] 1) an alkyl group as defined above, having from 1 to 5substituents, and preferably 1 to 3 substituents, selected from thegroup consisting of alkoxy, substituted alkoxy, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino,acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO—alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl; or

[0033] 2) an alkyl group as defined above that is interrupted by 1-20atoms independently chosen from oxygen, sulfur and NR^(a)-, where R^(a)is chosen from hydrogen, or optionally substituted alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryland heterocyclic; or

[0034] 3) an alkyl group as defined above that has both from 1 to 5substituents as defined above and is also interrupted by 1-20 atoms asdefined above.

[0035] One preferred alkyl substituent is hydroxy, exemplified byhydroxyalkyl groups, such as 2-hydroxyethyl, 3-hydroxypropyl,3-hydroxybutyl, 4-hydroxybutyl, and the like; dihydroxyalkyl groups(glycols), such as 2,3-dihydroxypropyl, 3,4-dihydroxybutyl,2,4-dihydroxybutyl, and the like; and those compounds known aspolyethylene glycols, polypropylene glycols and polybutylene glycols,and the like.

[0036] The term “alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, preferably having from 1 to 20carbon atoms, preferably 1-10 carbon atoms, more preferably 1-6 carbonatoms. This term is exemplified by groups such as methylene (—CH₂—),ethylene (—CH₂CH₂—), the propylene isomers (e.g., —CH₂CH₂CH₂—and—CH(CH₃)CH₂—) and the like.

[0037] The term “substituted alkylene” refers to:

[0038] (1) an alkylene group as defined above having from 1 to 5substituents selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy,oxyacylamino, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy,thioaryloxy, heteroaryl, heteroaryloxy, thioheteroaryloxy, heterocyclic,heterocyclooxy, thioheterocyclooxy, nitro, and —NR^(a)R^(b), whereinR^(a) and R^(b) may be the same or different and are chosen fromhydrogen, optionally substituted alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. Additionally,such substituted alkylene groups include those where two substituents onthe alkylene group are fused to form one or more cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclicor heteroaryl groups fused to the alkylene group; or

[0039] (2) an alkylene group as defined above that is interrupted by1-20 atoms independently chosen from oxygen, sulfur and NR¹-, whereR^(a) is chosen from hydrogen, optionally substituted alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryland heterocyclic, or groups selected from carbonyl, carboxyester,carboxyamide and sulfonyl; or

[0040] (3) an alkylene group as defined above that has both from 1 to 5substituents as defined above and is also interrupted by 1-20 atoms asdefined above.

[0041] Examples of substituted alkylenes are chloromethylene (—CH(Cl)—),aminoethylene (—CH(NH₂)CH₂—), methylaminoethylene ((—CH(NHMe)CH₂—),2-carboxypropylene isomers (—CH₂CH(CO²H)CH₂—), ethoxyethyl(—CH₂CH²O—CH₂CH₂—), ethylmethylaminoethyl (—CH₂CH₂N(CH₃)CH₂CH₂—),1-ethoxy-2-(2-ethoxy-ethoxy)ethane (—CH₂CH₂O—CH₂CH₂—OCH₂CH₂—OCH₂CH₂—),and the like.

[0042] The term “alkaryl” refers to the groups -optionally substitutedalkylene-optionally substituted aryl, where alkylene, substitutedalkylene, aryl and substituted aryl are defined herein. Such alkarylgroups are exemplified by benzyl, phenethyl and the like.

[0043] The term “alkoxy” refers to the groups alkyl-O—, alkenyl-O—,cycloalkyl-O—, cycloalkenyl-O—, and alkynyl-O—, where alkyl, alkenyl,cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferredalkoxy groups are alkyl-O—and include, by way of example, methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0044] The term “substituted alkoxy” refers to the groups substitutedalkyl-O—, substituted alkenyl-O—, substituted cycloalkyl-O—, substitutedcycloalkenyl-O—, and substituted alkynyl-O—where substituted alkyl,substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyland substituted alkynyl are as defined herein. One preferred substitutedalkoxy group is substituted alkyl-O, and includes groups such as—OCH₂CH₂OCH₃, PEG groups such as —O(CH₂CH₂O)_(x)CH₃, where x is aninteger of 2-20, preferably 2-10, and more preferably 2-5. Anotherpreferred substituted alkoxy group is —O—CH₂—(CH₂)_(y)—OH, where y is aninteger of 1-10, preferably 1-4.

[0045] The term “alkylalkoxy” refers to the groups -alkylene-O—alkyl,alkylene-O-substituted alkyl, substituted alkylene-O-alkyl andsubstituted alkylene-O-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.Preferred alkylalkoxy groups are alkylene-O-alkyl and include, by way ofexample, methylenemethoxy (—CH₂OCH₃), ethylenemethoxy (—CH₂CH₂OCH₃),n-propylene-iso-propoxy (—CH₂CH₂CH₂OCH(CH₃)₂), methylene-t-butoxy(—CH₂—O—C(CH3)₃) and the like.

[0046] The term “alkylthioalkoxy” refers to the group -alkylene-S-alkyl,alkylene-S-substituted alkyl, substituted alkylene-S-alkyl andsubstituted alkylene-S-substituted alkyl wherein alkyl, substitutedalkyl, alkylene and substituted alkylene are as defined herein.Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, byway of example, methylenethiomethoxy (—CH₂SCH₃), ethylenethiomethoxy(—CH₂CH₂SCH₃), n-propylene-iso-thiopropoxy (—CH₂CH₂CH₂SCH(CH₃)₂),methylene-t-thiobutoxy (—CH₂SC(CH₃)₃) and the like.

[0047] The term “alkenyl” refers to a monoradical of a branched orunbranched unsaturated hydrocarbon group preferably having from 2 to 20carbon atoms, more preferably 2 to 10 carbon atoms and even morepreferably 2 to 6 carbon atoms and having at least 1 and preferably from1-6 sites of vinyl unsaturation. Preferred alkenyl groups includeethenyl (—CH═CH₂), 1-propylene (—CH₂CH═CH₂), isopropylene (—C(CH₃)═CH₂),and the like.

[0048] The term “substituted alkenyl” refers to an alkenyl group asdefined above having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

[0049] The term “alkenylene” refers to a diradical of a branched orunbranched unsaturated hydrocarbon group preferably having from 2 to 20carbon atoms, more preferably 2 to 10 carbon atoms and even morepreferably 2 to 6 carbon atoms and having at least 1 and preferably from1-6 sites of vinyl unsaturation. This term is exemplified by groups suchas ethenylene (—CH═CH—), the propenylene isomers (e.g., —CH₂CH═CH—and—C(CH₃)═CH—) and the like.

[0050] The term “substituted alkenylene” refers to an alkenylene groupas defined above having from 1 to 5 substituents, and preferably from 1to 3 substituents, selected from the group consisting of alkoxy,substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substitutedamino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen,hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy,thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substitutedthioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl. Additionally,such substituted alkenylene groups include those where 2 substituents onthe alkenylene group are fused to form one or more cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,heterocyclic or heteroaryl groups fused to the alkenylene group.

[0051] The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, preferably having from 2 to 20 carbon atoms, morepreferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbonatoms and having at least 1 and preferably from 1-6 sites of acetylene(triple bond) unsaturation. Preferred alkynyl groups include ethynyl,(—C≡CH), propargyl (or propynyl, —C≡CCH₃), and the like.

[0052] The term “substituted alkynyl” refers to an alkynyl group asdefined above having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

[0053] The term “alkynylene” refers to a diradical of an unsaturatedhydrocarbon preferably having from 2 to 20 carbon atoms, more preferably2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms andhaving at least 1 and preferably from 1-6 sites of acetylene (triplebond) unsaturation. Preferred alkynylene groups include ethynylene(—C≡C—), propargylene (—CH₂—C≡C—) and the like.

[0054] The term “substituted alkynylene” refers to an alkynylene groupas defined above having from 1 to 5 substituents, and preferably 1 to 3substituents, selected from the group consisting of alkoxy, substitutedalkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

[0055] The term “acyl” refers to the groups HC(O)—, alkyl-C(O)—,substituted alkyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,alkenyl-C(O)—, substituted alkenyl-C(O)—, cycloalkenyl-C(O)—,substituted cycloalkenyl-C(O)—, aryl-C(O)—, heteroaryl-C(O)—andheterocyclic-C(O)— where alkyl, substituted alkyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,heteroaryl and heterocyclic are as defined herein.

[0056] The term “acylamino” or “aminocarbonyl” refers to the group—C(O)NRR where each R is independently hydrogen, alkyl, substitutedalkyl, aryl, heteroaryl, heterocyclic or where both R groups are joinedto form a heterocyclic group (e.g., morpholino) wherein alkyl,substituted alkyl, aryl, heteroaryl and heterocyclic are as definedherein.

[0057] The term “aminoacyl” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, orheterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl andheterocyclic are as defined herein.

[0058] The term “aminoacyloxy” or “alkoxycarbonylamino” refers to thegroup —NRC(O)OR where each R is independently hydrogen, alkyl,substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl,substituted alkyl, aryl, heteroaryl and heterocyclic are as definedherein.

[0059] The term “acyloxy” refers to the groups alkyl-C(O)O—, substitutedalkyl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—,aryl-C(O)O—, heteroaryl-C(O)O—, and heterocyclic-C(O)O— wherein alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl,and heterocyclic are as defined herein.

[0060] The term “aryl” refers to an unsaturated aromatic carbocyclicgroup of from 6 to 20 carbon atoms having a single ring (e.g., phenyl)or multiple condensed (fused) rings (e.g., naphthyl or anthryl).Preferred aryls include phenyl, naphthyl and the like.

[0061] Unless otherwise constrained by the definition for the arylsubstituent, such aryl groups can optionally be substituted with from 1to 5 substituents, preferably 1 to 3 substituents, selected from thegroup consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl,substituted cycloalkyl, substituted cycloalkenyl, amino, substitutedamino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.

[0062] The term “aryloxy” refers to the group aryl-O— wherein the arylgroup is as defined above including optionally substituted aryl groupsas also defined above.

[0063] The term “arylene” refers to the diradical derived from aryl(including substituted aryl) as defined above and is exemplified by1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and thelike.

[0064] The term “amino” refers to the group —NH₂.

[0065] The term “substituted amino refers to the group —NRR where each Ris independently selected from the group consisting of hydrogen, alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl,substituted alkynyl, aryl, heteroaryl and heterocyclic provided thatboth R's are not hydrogen.

[0066] The term “carboxyalkyl” or “alkoxycarbonyl” refers to the groups“—C(O)O-alkyl”, “—C(O)O-substituted alkyl”, “—C(O)O—cycloalkyl”,“—C(O)O-substituted cycloalkyl”, “—C(O)O-alkenyl”, “—C(O)O-substitutedalkenyl”, “—C(O)O—alkynyl” and “—C(O)O-substituted alkynyl” where alkyl,substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl,substituted alkenyl, alkynyl and substituted alkynyl are as definedherein.

[0067] The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to20 carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, and the like.

[0068] The term “substituted cycloalkyl” refers to cycloalkyl groupshaving from 1 to 5 substituents, and preferably 1 to 3 substituents,selected from the group consisting of alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

[0069] The term “cycloalkylene” refers to the diradical derived fromcycloalkyl as defined above and is exemplified by 1,1-cyclopropylene,1,2-cyclobutylene, 1,4-cyclohexylene and the like.

[0070] The term “substituted cycloalkylene” refers to the diradicalderived from substituted cycloalkyl as defined above.

[0071] The term “cycloalkenyl” refers to cyclic alkenyl groups of from 4to 20 carbon atoms having a single cyclic ring and at least one point ofinternal unsaturation. Examples of suitable cycloalkenyl groups include,for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and thelike.

[0072] The term “cycloalkenylene” refers to the diradical derived fromcycloalkenyl as defined above and is exemplified by1,2-cyclobut-1-enylene, 1,4-cyclohex-2-enylene and the like.

[0073] The term “substituted cycloalkenyl” refers to cycloalkenyl groupshaving from 1 to 5 substituents, and preferably 1 to 3 substituents,selected from the group consisting of alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino,aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl,aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl,—SO-aryl, —SO-heteroaryl, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryland —SO₂-heteroaryl.

[0074] The term “substituted cycloalkenylene” refers to the diradicalderived from substituted cycloalkenyl as defined above.

[0075] The term “halo” or “halogen” refers to fluoro, chloro, bromo andiodo.

[0076] The term “heteroaryl” refers to an aromatic group comprising 1 to15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogenand sulfur within at least one ring.

[0077] Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents, preferably 1 to 3 substituents, selected from thegroup consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl,substituted alkoxy, substituted alkenyl, substituted alkynyl,substituted cycloalkyl, substituted cycloalkenyl, amino, substitutedamino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl,carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy,heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, —SO-alkyl,—SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl,—SO₂-substituted alkyl, —SO₂-aryl, —SO₂-heteroaryl and trihalomethyl.Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro,trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a singlering (e.g., pyridyl or furyl) or multiple condensed rings (e.g.,indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl,pyrrolyl and furyl.

[0078] The term “heteroaryloxy” refers to the group heteroaryl-O—.

[0079] The term “heteroarylene” refers to the diradical group derivedfrom heteroaryl (including substituted heteroaryl), as defined above,and is exemplified by the groups 2,6-pyridylene, 2,4-pyridiylene,1,2-quinolinylene, 1,8-quinolinylene, 1,4-benzofuranylene,2,5-pyridnylene, 2,5-indolenyl and the like.

[0080] The term “heterocycle” or “heterocyclic” refers to a monoradicalsaturated or unsaturated group having a single ring or multiplecondensed rings, having from 1 to 40 carbon atoms and from 1 to 10hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen,sulfur, phosphorus, and/or oxygen within the ring.

[0081] Unless otherwise constrained by the definition for theheterocyclic substituent, such heterocyclic groups can be optionallysubstituted with 1 to 5, and preferably 1 to 3 substituents, selectedfrom the group consisting of alkoxy, substituted alkoxy, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl,carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino,nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, —SO₂-substituted alkyl, —SO₂-aryl and —SO₂-heteroaryl. Suchheterocyclic groups can have a single ring or multiple condensed rings.Preferred heterocyclics include morpholino, piperidinyl, and the like.

[0082] Examples of nitrogen heterocycles and heteroaryls include, butare not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, phenanthroline, isothiazole, phenazine,isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline,piperidine, piperazine, indoline, morpholino, piperidinyl,tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containingheterocycles.

[0083] The term “heterocyclooxy” refers to the group heterocyclic-O—.

[0084] The term “thioheterocyclooxy” refers to the groupheterocyclic-SO—.

[0085] The term “heterocyclene” refers to the diradical group formedfrom a heterocycle, as defined herein, and is exemplified by the groups2,6-morpholino, 2,5-morpholino and the like.

[0086] The term “oxyacylamino” or “aminocarbonyloxy” refers to the group—OC(O)NRR where each R is independently hydrogen, alkyl, substitutedalkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substitutedalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0087] The term “spiro-attached cycloalkyl group” refers to a cycloalkylgroup attached to another ring via one carbon atom common to both rings.

[0088] The term “thiol” refers to the group —SH.

[0089] The term “thioalkoxy” refers to the group —SO-alkyl.

[0090] The term “substituted thioalkoxy” refers to the group—S-substituted alkyl.

[0091] The term “thioaryloxy” refers to the group aryl—S— wherein thearyl group is as defined above including optionally substituted arylgroups also defined above.

[0092] The term “thioheteroaryloxy” refers to the group heteroaryl—S—wherein the heteroaryl group is as defined above including optionallysubstituted aryl groups as also defined above.

[0093] The term “carboxyamides” include primary carboxyamides (CONH₂),secondary carboxyamides (CONHR′) and tertiary carboxyamides (CONR′R″),where R′ and R″ are the same or different substituent groups chosen fromalkyl, alkenyl, alkynyl, alkoxy, aryl, a heterocyclic group, afunctional group as defined herein, and the like, which themselves maybe substituted or unsubstituted.

[0094] “Carboxyamidealkyl” means a carboxyamide as defined aboveattached to an optionally substituted alkylene group as defined above.

[0095] The term “saccharide” includes oxidized, reduced or substitutedsaccharides, including hexoses such as D-glucose, D-mannose orD-galactose; pentoses such as D-ribose or D-arabinose; ketoses such asD-ribulose or D-fructose; disaccharides such as sucrose, lactose, ormaltose; derivatives such as acetals, amines, and phosphorylated sugars;oligosaccharides; as well as open chain forms of sugars, and the like.Examples of amine-derivatized sugars are galactosamine, glucosamine, andsialic acid.

[0096] The term “site-directing molecule” refers to a molecule having anaffinity for a biological receptor or for a nucleic acid sequence.Exemplary site-directing molecules useful herein include, but are notlimited to, polydeoxyribonucleotides, oligodeoxyribonucleotides,polyribonucleotide analogs, oligoribonucleotide analogs, polyamidesincluding peptides having affinity for a biological receptor andproteins such as antibodies, steroids and steroid derivatives, hormonessuch as estradiol or histamine, hormone mimics such as morphine, andfurther macrocycles such as sapphyrins and rubyrins. Theoligonucleotides may be derivatized at the bases, the sugars, the endsof the chains, or at the phosphate groups of the backbone to promote invivo stability. Modifications of the phosphate groups are preferred inone embodiment since phosphate linkages are sensitive to nucleaseactivity. Presently preferred derivatives are the methylphosphonates,phosphotriesters, phosphorothioates, and phosphoramidates. Additionally,the phosphate linkages may be completely substituted with non-phosphatelinkages such as amide linkages. Appendages to the ends of theoligonucleotide chains also provide exonuclease resistance. Sugarmodifications may include groups, such as halo, alkyl, alkenyl or alkoxygroups, attached to an oxygen of a ribose moiety in a ribonucleotide. Ina preferred embodiment, the group will be attached to the 2′ oxygen ofthe ribose. In particular, halogen moieties such as fluoro may be used.The alkoxy group may be methoxy, ethoxy or propoxy. The alkenyl group ispreferably allyl. The alkyl group is preferably a methyl group and themethyl group is attached to the 2′ oxygen of the ribose. Other alkylgroups may be ethyl or propyl. It is understood that the terms“nucleotide”, “polynucleotide” and “oligonucleotide”, as used herein andin the appended claims, refer to both naturally-occurring and syntheticnucleotides, poly- and oligonucleotides and to analogs and derivativesthereof such as methylphosphonates, phosphotriesters, phosphorothioates,phosphoramidates and the like. Deoxyribonucleotides, deoxyribonucleotideanalogs and ribonucleotide analogs are contemplated as site-directingmolecules in the present invention. The term “texaphyrin-oligonucleotideconjugate” means that an oligonucleotide is attached to the texaphyrinin a 5′ or a 3′ linkage, or in both types of linkages to allow thetexaphyrin to be an internal residue in the conjugate. It can also referto a texaphyrin that is linked to an internal base of theoligonucleotide. The oligonucleotide or other site-directing moleculemay be attached either directly to the texaphyrin or to the texaphyrinvia a linker or a couple of variable length.

[0097] The term “catalytic group” means a chemical functional group thatassists catalysis by acting as a general acid, Bronsted acid, generalbase, Bronsted base, nucleophile, or any other means by which theactivation barrier to reaction is lowered. Exemplary catalytic groupscontemplated include, but are not limited to, imidazole; guanidine;substituted saccharides such as D-glucosamine, D-mannosamine,D-galactosamine, D-glucamine and the like; amino acids such asL-histidine and L-arginine; derivatives of amino acids such ashistamine; polymers of amino acids such as poly-L-lysine, (LysAla),(LysLeuAla)_(n) where n is from 1-30 or preferably 1-10 or morepreferably 2-7 and the like; derivatives thereof; and metallotexaphyrincomplexes.

[0098] A “chemotherapeutic agent” may be, but is not limited to, one ofthe following: an alkylating agent such as a nitrogen mustard, anethyleneimine or a methylmelamine, an alkyl sulfonate, a nitrosourea, ora triazene; an antimetabolite such as a folic acid analog, a pyrimidineanalog, or a purine analog; a natural product such as a vinca alkaloid,an epipodophyllotoxin, an antibiotic, an enzyme, taxane, or a biologicalresponse modifier; miscellaneous agents such as a platinum coordinationcomplex, an anthracenedione, an anthracycline, a substituted urea, amethyl hydrazine derivative, or an adrenocortical suppressant; or ahormone or an antagonist such as an adrenocorticosteroid, a progestin,an estrogen, an antiestrogen, an androgen, an antiandrogen, or agonadotropin-releasing hormone analog. Chemotherapeutic agents are usedin the treatment of cancer and other neoplastic tissue. Preferably, thechemotherapeutic agent is a nitrogen mustard, an epipodophyllotoxin, anantibiotic, or a platinum coordination complex. A more preferredchemotherapeutic agent is bleomycin, doxorubicin, taxol, taxotere,etoposide, 4-OH cyclophosphamide, cisplatin, or platinum coordinationcomplexes analogous to cisplatin. A presently preferred chemotherapeuticagent is doxorubicin, taxol, taxotere, cisplatin, or Pt complexesanalogous to cisplatin. Various chemotherapeutic agents, their targetdiseases, and treatment protocols are presented in, for example, Goodmanand Gilman's The Pharmacological Basis of Therapeutics, Ninth Ed.,Pergamon Press, Inc., 1990; and Remington: The Science and Practice ofPharmacy, Mack Publishing Co., Easton, Pa., 1995; both of which areincorporated by reference herein.

[0099] A site directing molecule, or a group having or catalytic orchemotherapeutic activity, identified above by the symbol Y, may becovalently coupled to any position on a metallotexaphyrin by a covalentbond or by a linker (identified above by the symbol X). The term“linker” as used herein means a group that covalently connects Y to ametallotexaphyrin, and may be, for example, alkylene, alkenylene,alkynylene, arylene, ethers, PEG moieties, and the like, all of whichmay be optionally substituted. Examples of reactions to form a covalentlink include reaction between an amine (on either the molecule Y or X)with a carboxylic acid (on the corresponding X or Y) to form an amidelink. Similar reactions well known in the art are described in standardorganic chemistry texts such as J. March, “Advanced Organic Chemistry”,4^(th) Edition, (Wiley-Interscience (New York), 1992.

[0100] The term “macrocycle” as used herein refers to a class ofpolypyrrole macrocycles that are capable of forming stable complexeswith metals by incorporating a metal (as its cation) within a centralbinding cavity (core) of the macrocycle, and the anions associated withthe metal cation are found above and below the core; these anions areknown as apical ligands. This class of macrocycles includes porphyrins,the so-called “expanded porphyrins”, and similar structures. Specificexamples are porphyrins, porphyrin isomers, porphyrin-like macrocycles,benzophyrins, texaphyrins, alaskaphyrins, sapphyrins, rubyrins,porphycenes, chlorins, benzochlorins, and purpurins.

[0101] The term “apical ligand” refers to an anion that binds to thecore metal of the MTD with de-localized electrostatic bonds. The numberof apical ligands (n) is defined as an integer of 1-5. It should benoted that the apical ligands act to neutralize the charge on themetallotexaphyrin. Thus, typically n is 1 when M is a divalent cation,and n is 2 when M is a trivalent cation (because the core itselfneutralizes one unit charge). However, if any of R¹, R², R³, R⁴, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, and R¹² is capable of forming an acid addition salt,for example a carboxylate or a phosphate, then n will decreaseappropriately. It is also possible that the apical ligands could havetwo functionalities capable of forming an anion, for example adicarboxylic acid, and such ligands are intended to be within the scopeof the invention.

[0102] In general, any molecule containing a carboxylic acid orphosphate may be used as an apical ligand, for example biomolecules,including lipoproteins, estradiol and amino acids, carboxylates of sugarderivatives, such as gluconic acid or glucoronic acid, cholesterolderivatives such as cholic acid and deoxycholic acid, PEG acids,organophosphates, such as methylphosphonic acid and phenylphosphonicacid, and phosphoric acid or other inorganic acids, and the like, orsulfonic acid derivatives such as methanesulfonic acid, ethanesulfonicacid. or “carboxylic acid derivatives”, which term refers to compoundsof the formula R—CO₂H, in which R is optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl, oroptionally substituted aryl, as defined above. Preferred are gluconicand glucuronic acid, and those carboxylic acid derivatives where R isoptionally substituted alkyl, for example acids of 1-20 carbon atoms,such as formic acid, acetic acid, propionic acid, butyric acid,pentanoic acid, 3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic acid,methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid, malicacid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaricacid, citric acid, and the like. Also preferred are those carboxylicacid derivatives where R is aryl, in particular where R is optionallysubstituted phenyl, for example benzoic acid, salicylic acid,3-fluorobenzoic acid, 4-aminobenzoic acid, cinnamic acid, mandelic acid,p-toluene-sulfonic acid,2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methyl-propanoicacid, and the like.

[0103] It should be noted that the term “apical ligands” as associatedwith metallotexaphyrins was employed in U.S. Pat. No. 4,935,498, inwhich the apical ligands were said to include pyridine andbenzimidazole, and in U.S. Pat. No. 5,801,229, in which the apicalligands were said to include acetate, chloride, nitrate, hydroxy, water,and methanol. However, pyridine, benzimidazole, water, and methanol arenot apical ligands as defined herein, since they are not anionsassociated with a metal cation; for the purpose of this application,such derivatives are referred to as “coordination complexes.”

[0104] As to any of the above groups that contain one or moresubstituents, it is understood, of course, that such groups do notcontain any substitution or substitution patterns which are stericallyimpractical and/or synthetically non-feasible. In addition, thecompounds of this invention include all stereochemical isomers arisingfrom the substitution of these compounds.

[0105] The term “compound of Formula I” is intended to encompass themetallotexaphyrins of the invention as disclosed, coordination complexesof the compounds of Formula I, and/or the pharmaceutically acceptablesalts of such compounds.

[0106] The term “therapeutically effective amount” refers to that amountof an MTD of Formula I that is sufficient to effect treatment, asdefined below, when administered to a mammal in need of such treatment.The therapeutically effective amount will vary depending upon thesubject and disease condition being treated, the weight and age of thesubject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willprovide an image for detection by any one of the imaging methodsdescribed herein. The specific dose will vary depending on theparticular compound of Formula I chosen, the dosing regimen to befollowed, timing of administration, the tissue to be imaged, and thephysical delivery system in which it is carried.

[0107] “Texaphyrin” means an aromatic pentadentate macrocyclic expandedporphyrins, also described as an aromatic benzannulene containing both18π- and 22π-electron delocalization pathways. Texaphyrins andwater-soluble texaphyrins, method of preparation and various uses havebeen described in U.S. Pat. Nos. 4,935,498, 5,162,509, 5,252,720,5,256,399, 5,272,142, 5,292,414, 5,369,101, 5,432,171, 5,439,570,5,451,576, 5,457,183, 5,475,104, 5,504,205, 5,525,325, 5,559,207,5,565,552, 5,567,687, 5,569,759, 5,580,543, 5,583,220, 5,587,371,5,587,463, 5,591,422, 5,594,136, 5,595,726, 5,599,923, 5,599,928,5,601,802, 5,607,924, 5,622,946, and 5,714,328; PCT publications WO90/10633, 94/29316, 95/10307, 95/21845, 96/09315, 96/40253, 96/38461,97/26915, 97/35617, 97/46262, and 98/07733; allowed U.S. patentapplications Ser. Nos. 08/458,347, 08/591,318, and 08/914,272; andpending U.S. patent application Ser. Nos. 08/763,451, 08/903,099,08/946,435, 08/975,090, 08/975,522, 08/988,336, and 08/975,526; each ofwhich are herein incorporated by reference in their entirety.

[0108] Texaphyrins are illustrated as a compound of Formula I above. Twopositions on the compound of Formula I are designated as R¹, and twopositions are designated as R⁴. This is because, in general, thedisclosed methods of synthesis of texaphyrins leads to the samesubstituent at R¹, and the same substituents at R⁴. However, it shouldbe noted that methods of synthesis of texaphyrins in which thesepositions are the same or different are described in U.S. patentapplication Ser. No. 60/229,247, filed on Aug. 30, 2000, the completedisclosure of which is hereby incorporated by reference in its entirety.

[0109] “Sapphyrins” and water-soluble sapphyrins and methods ofpreparation have been described in U.S. Pat. Nos. 5,041,078; 5,120,411;5,159,065; 5,302,714; 5,457,195; 5,530,123; 5,543,514; and 5,672,490;and in International Publn. WO 94/09003; all of which are incorporatedherein by reference in its entirety.

[0110] “Optional” or “optionally” means that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where said event or circumstance occurs and instancesin which it does not.

[0111] “Water soluble” means soluble in an aqueous medium to about 1 mMor more.

[0112] As used herein, “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the like.The use of such media and agents for pharmaceutically active substancesis well known in the art. Except insofar as any conventional media oragent is incompatible with the active ingredient, its use in thetherapeutic compositions is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

[0113] The term “treatment” or “treating” means any treatment of adisease in a mammal, including:

[0114] (i) preventing the disease, that is, causing the clinicalsymptoms of the disease not to develop;

[0115] (ii) inhibiting the disease, that is, arresting the developmentof clinical symptoms; and/or

[0116] (iii) relieving the disease, that is, causing the regression ofclinical symptoms.

[0117] The term “pharmaceutically acceptable salt” refers to salts whichretain the biological effectiveness and properties of the MTDs of thisinvention and which are not biologically or otherwise undesirable. Inmany cases, the compounds of this invention are capable of forming acidand/or base salts by virtue of the presence of amino and/or carboxylgroups or groups similar thereto. Pharmaceutically acceptable baseaddition salts can be prepared from inorganic and organic bases. Saltsderived from inorganic bases, include by way of example only, sodium,potassium, lithium, ammonium, calcium and magnesium salts. Salts derivedfrom organic bases include, but are not limited to, salts of primary,secondary and tertiary amines, such as alkyl amines, dialkyl amines,trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines,tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines,trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl)amines, tri(substituted alkenyl) amines, cycloalkyl amines,di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkylamines, disubstituted cycloalkyl amine, trisubstituted cycloalkylamines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl)amines, substituted cycloalkenyl amines, disubstituted cycloalkenylamine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines,triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroarylamines, heterocyclic amines, diheterocyclic amines, triheterocyclicamines, mixed di- and tri-amines where at least two of the substituentson the amine are different and are selected from the group consisting ofalkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,heteroaryl, heterocyclic, and the like. Also included are amines wherethe two or three substituents, together with the amino nitrogen, form aheterocyclic or heteroaryl group.

[0118] Specific examples of suitable amines include, by way of exampleonly, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol,tromethamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,N-alkylglucamines, theobromine, purines, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

[0119] Pharmaceutically acceptable acid addition salts may be preparedfrom inorganic and organic acids. Salts derived from inorganic acidsinclude hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

Nomenclature

[0120] The naming and numbering of the MTDs of the present invention isillustrated with a representative compound texaphyrin of Formula I, ALis gluconate (Gluc), and the metal M is lutetium (Lu), depicted below asa compound of Formula IA:

[0121] This compound can be named in a variety of ways (e.g. dependingon the origination of the numbering). Examples of alternative names forthis compound are:

[0122] The lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxy propyl)-16,17-bis[2-[2-(2methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8.11).0 ^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis gluconate; orBis(gluconato-O)[9,10-diethyl-20,21-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-4,15-dimethyl-8,11-imino-3,6,16,13-dinitrilo-1,18-benzodiazacyclooeicosine-5,14-dipropanolato-N¹, N¹⁸, N²³, N²⁴, N²⁵]lutetium; or

[0123] Lutetium texaphyrin bis-gluconate; or

[0124] Lu-Tex bis-gluconate; or

[0125] Lu-Tex digluconate.

[0126] For the purposes of this specification, the format(Metal)-Macrocycle-Apical Ligand (such as LuTex diacetate or LuTexbisacetate, or LuTex bis-gluconate) is preferred.

Synthetic Reaction Parameters

[0127] The terms “solvent”, “inert organic solvent” or “inert solvent”mean a solvent inert under the conditions of the reaction beingdescribed in conjunction therewith [including, for example, benzene,toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide(“DMF”), chloroform, methylene chloride (or dichloromethane), diethylether, methanol, pyridine and the like]. Unless specified to thecontrary, the solvents used in the reactions of the present inventionare inert organic solvents.

[0128] The term “q.s.” means adding a quantity sufficient to achieve astated function, e.g., to bring a solution to the desired volume (i.e.,100%).

[0129] Unless specified to the contrary, the reactions described hereintake place at atmospheric pressure within a temperature range from 5° C.to 100° C. (preferably from 10° C. to 50° C.; most preferably at about“room” or “ambient” temperature, e.g., about 20° C.).

[0130] Further, unless otherwise specified, the reaction times andconditions are intended to be approximate, e.g., taking place at aboutatmospheric pressure within a temperature range of about 5° C. to about100° C. (preferably from about 10° C. to about 50° C.; most preferablyabout 20° C.) over a period of about 1 to about 10 hours (preferablyabout 5 hours). Parameters given in the Examples are intended to bespecific, not approximate.

[0131] Isolation and purification of the compounds and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure, such as crystallization, distillation,filtration, extraction, column chromatography, solvent evaporation underreduced pressure; thin layer chromatography, thick layer chromatography,preparative low or high pressure liquid chromatography, or a combinationof these procedures. Specific illustrations of suitable separation andisolation procedures can be had by reference to the exampleshereinbelow. However, other equivalent separation or isolationprocedures can, of course, also be used.

Synthesis of the Compounds of Formula I

[0132] Alternative syntheses of the compounds of Formula I are describedbelow with reference to Reaction Schemes 1 and 2.

[0133] Reaction Scheme 1 illustrates a preferred synthesis of thecompounds of Formula I. A texaphyrin with the desired apical ligand(s)(a compound of Formula I) is obtained by an exchange reaction between ametallotexaphyrin having displaceable apical ligands, preferablyacetate, and an appropriately charged ion exchange resin. To this end,the desired apical ligand (AL)H is bound to an ion exchange resin, andthe ion exchange resin complex thus obtained is reacted with thestarting metallotexaphyrin having displaceable apical ligands. Theproduct is separated and purified conventionally.

[0134] in which T is a texaphyrin, M is a metal, (AL₁) represents theapical ligand associated with the starting texaphyrin, (AL) representsthe desired apical ligand that replaces (AL₁), n is an integer of 1-5,and the ion exchange resin is a commercially available resin such asAmbersep® 900 (OH) anion exchange resin.

[0135] For example, starting with a compound in which T is thetexaphyrin illustrated as the compound of Formula IA, as its bisacetate, and reacting with an ion exchange resin prepared with gluconicacid (i.e., (AL)H is gluconic acid), the product obtained is LuTex bisgluconate, a compound of Formula I.

[0136] Reaction Scheme 2 illustrates an alternative synthesis of thecompounds of Formula I, utilizing an in-situ exchange of apical ligands.A metallotexaphyrin having one or more apical ligands, preferablyacetate, is reacted with an excess of the desired apical ligand,optionally at raised temperatures.

[0137] in which T is a texaphyrin, M is a metal, (AL₁) represents theapical ligand associated with M of the starting texaphyrin, (AL)represents the desired apical ligand that replaces (AL₁), and n is aninteger of 1-5.

[0138] For example, starting with a compound in which T is thetexaphyrin illustrated as the compound of Formula IA, as its bisacetate, and reacting with an excess of gluconic acid (i.e., (AL)H isgluconic acid), the product obtained is LuTex bis gluconate, a compoundof Formula IA. The compound of Formula I is then separated from themixture conventionally.

[0139] Reaction Scheme 3 shows the preparation of a mixture of compoundsof Formula.

[0140] in which T is a texaphyrin, M is a metal, (AL₁) represents theapical ligand associated with M of the starting texaphyrin, (AL₂) and(AL3) represent a mixture of desired apical ligands that replaces (AL₁),and n is an integer of 1-5.

[0141] This reaction can be carried out as in Reaction Scheme I (usingan ion exchange resin), or as shown in Reaction Scheme 2 (using a largeexcess of a mixture of the apical ligands). Alternatively, the reactioncan be carried out in a biphasic mixture, for example in a methylenechloride/water mixture.

[0142] An alternative method of preparing the compounds of the inventionis to first prepare a metal-apical ligand M(Al)_(n), where M, Al, and nare as defined above, and then reacting this metal complex with atexaphyrin, and an oxidizing agent, for example oxygen, to give ametallated texaphyrin of Formula I.

[0143] Substituting a metallomacrocycle, as defined above, for ametallotexaphyrin in the above reaction schemes and carrying out thereaction in a similar manner provides metallomacrocycle derivativeshaving different apical ligands.

Starting Materials

[0144] The anion exchange resin is commercially available, e.g., fromRohm and Haas. The desired apical ligands, such as gluconic acid, arelikewise commercially available or may be readily prepared by thoseskilled in the art using commonly employed synthetic methodology.

Preferred Compounds

[0145] Preferred are the compounds of Formula I in which M is a divalentor trivalent metal, R¹ is hydroxyalkyl (in which alkyl preferably has1-10 carbon atoms), R², R³ and R⁴ are alkyl (preferably of 1-6 carbonatoms), R⁷ and R⁸ are substituted alkoxy (in which alkoxy preferably has1-20 carbon atoms), and n is 1-4. R⁵, R⁶, R⁹, R¹⁰, R¹¹ and R¹² arehydrogen or alkyl of 1-6 carbon atoms.

[0146] More preferred are the compounds of Formula I where M is lutetiumor gadolinium, R¹ is 2-hyrdoxyethyl or 3-hydroxypropyl, R², R³ and R⁴are methyl or ethyl, R⁷ and R⁸ are 2-[2-(2-methoxyethoxy)ethoxy]ethoxy],and n is 2. R⁵, R⁶, R⁹, R¹⁰, R¹¹, and R¹² are preferably hydrogen ormethyl. Most preferred are the following compounds:

[0147] The lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1.^(3,6).1^(8,11).0^(14,19)]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis gluconate;

[0148] The lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis glucoronate;

[0149] The lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaene bis formate;

[0150] The lutetium (III complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]-heptacosa-1,3,5,7,9,1(27),12,14,16,18,20,22(25), 23-tridecaene bis benzoate;

[0151] The lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis methylvalerate;

[0152] The lutetium (III) complexof:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6.).1^(8,11).0^(14,19)]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaene bis deoxycholate;

[0153] The lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis 3,6,9-trioxodecanoate;

[0154] The lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6.) ^(8,11)0.^(14,19)]-heptacosa-1,3,5,7,9,1 (27),12,14,16,18,20,22(25),23-tridecaene bis 3,6-dioxoheptanoate;

[0155] The lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(81,1).0^(14,19)]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene methylphosphonate;

[0156] The lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6.).1^(8,11).0^(14,1 9)]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene phenylphosphonate; and

[0157] The lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy] ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]-heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis-cholate.

Preferred Processes and Last Steps

[0158] The MTDs of the present invention can be prepared according tothe following last steps:

[0159] I. Contacting a metellotexaphyrin of the formula(T-M)^(n+)-(AL¹)_(n) with an Ion Exchange Resin-(AL) complex, to give(T-M)^(n+)-(AL)_(n), a product of Formula I; in which T is a texaphyrin,M is a divalent or trivalent metal, (AL¹) represents the apical ligandassociated with M of the starting texaphyrin, (AL) represents the apicalligand that replaces (AL¹), n is 1 or 2, and the ion exchange resin is acommercially available resin such as Ambersep® 900 (OH) anion exchangeresin.

[0160] 2. Contacting a metallotexaphyrin of the formula(T-M)^(n+)-(AL¹)_(n) with an excess of (AL)H ligand, to give(T-M)^(n+)-(AL)_(n), a product of Formula I.

[0161] 3. Contacting a metallotexaphyrin of the formula(T-M)^(n+)-(AL¹)_(n) with a mixture of (AL²)H and (AL³ )H ligands, togive a mixture of (T-M)^(n+)-(AL²)_(n), (T-M)^(n+)-(AL³)_(n), and(T-M)^(n+)-(AL²)(AL³), a mixture of products of Formula I.

[0162] 4. Contacting a metallotexaphyrin of the formula(T-M)^(n+)-(AL¹)_(n) with a reverse phase chromatography absorptioncolumn, contacting the column with a salt of the apical ligand (AL), andeluting with a suitable solvent, for example methanol, to give(T-M)^(n+)-(AL)_(n) a product of Formula I.

Utility, Testing and Administration General Utility

[0163] The MTDs of the present invention are effective in the treatmentof conditions known to respond to metallotexaphyrin therapy, includingdiseases characterized by neoplastic tissue, (e.g. the cancers sarcoma,lymphoma, leukemia, carcinoma, brain metastases, glioma, glioblastoma,cancer of the prostate, melanoma, and the like), cardiovascular diseases(e.g., atherosclerosis, intimal hyperplasia and restenosis) and otheractivated macrophage-related disorders including autoimmune diseases(e.g., rheumatoid arthritis, Sjogrens, scleroderma, systemic lupuserythematosus, non-specific vasculitis, Kawasaki's disease, psoriasis,Type I diabetes, pemphigus vulgaris, multiple sclerosis), granulomatousdiseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis,Wegener's granulomatosus), inflammatory diseases (e.g., inflammatorylung diseases such as interstitial pneumonitis and asthma, inflammatorybowel disease such as Crohn's disease, and inflammatory arthritis), intransplant rejection (e.g., in heart/lung transplants) and in ophthalmicdiseases that result from undesired neovascularization, in particularage-related macular degeneration.

Testing

[0164] Activity testing is conducted as described in those patents andpatent applications incorporated by reference above, and in thefollowing references, and by modifications thereof. The MTDs of FormulaI have been shown to have various in vitro and in vivo activity. Seee.g. Young et al., Methods for Cancer Chemosensitization, and U.S. Pat.No. 5,776,925.

[0165] Determination of the various physicochemical characteristics ofeach MTD can be performed, and are apparent to one skilled in the artand are detailed in, for example, Pharmaceutical Dosage Forms:Parenteral Medications vol. 1, Marcel Dekker Inc., New York, N.Y.,2^(nd) Edition, 1992. The generally accepted tests performed todetermine the MTD's characteristics include, for example: determinationof solubility, the partition coefficient, the extinction coefficient,and the solution pH of the MTD.

Pharmaceutical Compositions

[0166] The MTDs of Formula I are usually administered in the form ofpharmaceutical compositions. This invention therefore providespharmaceutical compositions that contain, as the active ingredient, oneor more of the MTDs of Formula I, or a pharmaceutically acceptable saltAND/or coordination complex thereof, and one or more pharmaceuticallyacceptable excipients, carriers, including inert solid diluents andfillers, diluents, including sterile aqueous solution and variousorganic solvents, permeation enhancers, solubilizers and adjuvants. TheMTDs may be administered alone or in combination with other therapeuticagents. Such compositions are prepared in a manner well known in thepharmaceutical art (see, e.g., Remington's Pharmaceutical Sciences, MacePublishing Co., Philadelphia, Pa. 17^(th) Ed. (1985) and “ModernPharmaceutics”, Marcel Dekker, Inc. 3^(rd) Ed. (G. S. Banker & C. T.Rhodes, Eds.).

Administration

[0167] The MTDs of Formula I may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference above, including rectal,buccal, intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer, with parenteral and intra-arterial administrationbeing preferred, and intra-arterial being more preferred.

[0168] One preferred mode for administration is parental, particularlyby injection. The forms in which the novel compositions of the presentinvention may be incorporated for administration by injection includeaqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.Aqueous solutions in saline are also conventionally used for injection,but less preferred in the context of the present invention. Ethanol,glycerol, propylene glycol, liquid polyethylene glycol, and the like(and suitable mixtures thereof), cyclodextrin derivatives, and vegetableoils may also be employed. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like.

[0169] It has been discovered that texaphyrins have a tendency toaggregate in aqueous solution, which potentially decreases theirsolubility. Aggregation (self-association) of polypyrrolic macrocycliccompounds, including porphyrins, sapphyrins, texaphyrins, and the like,is a common phenomenon in water solution as the result of strongintermolecular van der Waals attractions between these flat aromaticsystems. Aggregation may significantly alter the photochemicalcharacteristics of the macrocycles in solution, which is shown by largespectral changes, decrease in extinction coefficient, etc.

[0170] It has been found that addition of a carbohydrate, saccharide,polysaccharide, or polyuronide to the formulation decreases the tendencyof the texaphyrin to aggregate, thus increasing the solubility of thetexaphyrin in aqueous media. Preferred anti-aggregation agents aresugars, in particular mannitol, dextrose or glucose, preferably mannitolof about 2-8% concentration, more preferably about 5% concentration.These aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. In thisconnection, the sterile aqueous media that can be employed will be knownto those of skill in the art in light of the present disclosure.

[0171] Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin. Theseparticular aqueous solutions are especially suitable for intra-arterial,intravenous, intramuscular, subcutaneous and intraperitonealadministration. In this connection, sterile aqueous media that can beemployed will be known to those skilled in the art in light of thepresent disclosure.

[0172] Sterile injectable solutions are prepared by incorporating theactive MTDs in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

[0173] MTDs of Formula I may be impregnated into a stent by diffusion,for example, or coated onto the stent such as in a gel form, forexample, using procedures known to one of skill in the art in light ofthe present disclosure.

[0174] Oral administration is another route for administration of theMTDs of this invention. Preferred is oral administration via capsule orenteric coated tablets, or the like, which prevent degradation of theMTDs of the invention in the stomach. In making the pharmaceuticalcompositions that include at least one MTD of Formula I, the activeingredient is usually diluted by an excipient and/or enclosed withinsuch a carrier that can be in the form of a capsule, sachet, paper orother container. When the excipient serves as a diluent, in can be asolid, semi-solid, or liquid material (as above), which acts as avehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, sterile injectable solutions, and sterile packagedpowders.

[0175] Some examples of suitable excipients include lactose, dextrose,sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate,alginates, tragacanth, gelatin, calcium silicate, microcrystallinecellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, andmethyl cellulose. The formulations can additionally include: lubricatingagents such as talc, magnesium stearate, and mineral oil; wettingagents; emulsifying and suspending agents; preserving agents such asmethyl- and propylhydroxy-benzoates; sweetening agents; and flavoringagents.

[0176] The compositions of the invention can be formulated so as toprovide quick, sustained or delayed release of the active ingredientafter administration to the patient by employing procedures known in theart. Controlled release drug delivery systems for oral administrationinclude osmotic pump systems and dissolutional systems containingpolymer-coated reservoirs or drug-polymer matrix formulations. Examplesof controlled release systems are given in U.S. Pat. Nos. 3,845,770;4,326,525; 4,902514; and 5,616,345. Another preferred formulation foruse in the methods of the present invention employs transdermal deliverydevices (“patches”). Such transdermal patches may be used to providecontinuous or discontinuous infusion of the MTDs of the presentinvention in controlled amounts. The construction and use of transdermalpatches for the delivery of pharmaceutical agents is well known in theart. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

[0177] The compositions are preferably formulated in a unit dosage form.The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient (e.g., a tablet, capsule, ampoule).The active MTD is effective over a wide dosage range and is generallyadministered in a pharmaceutically effective amount. Preferably, fororal administration, each dosage unit contains from 10 mg to 2 g of anMTD of Formula I, and for parenteral administration, preferably from 10to 700 mg of an MTD of Formula I, preferably about 350 mg. It will beunderstood, however, that the amount of the MTD actually administeredwill be determined by a physician, in the light of the relevantcircumstances, including the condition to be treated, the chosen routeof administration, the actual compound administered and its relativeactivity, the age, weight, and response of the individual patient, theseverity of the patient's symptoms, and the like.

[0178] For preparing solid compositions such as tablets, the principalactive ingredient is mixed with a pharmaceutical excipient to form asolid preformulation composition containing a homogeneous mixture of anMTD of the present invention. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules.

[0179] The tablets or pills of the present invention may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can comprise an inner dosage and anouter dosage component, the latter being in the form of an envelope overthe former. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

[0180] Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably the compositions are administered by the oral or nasalrespiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine.Solution, suspension, or powder compositions may be administered,preferably orally or nasally, from devices that deliver the formulationin an appropriate manner.

[0181] The MTDs disclosed herein can be used both diagnostically (e.g.magnetic resonance or fluorescence imaging to detect the presence of adisease) and therapeutically (to treat that disease).

Activation Means

[0182] The compounds of the invention to be used will be administered ina therapeutically effective amount, employing a method of administrationand a pharmaceutical formulation as discussed above, and optionally ameans of activation of the compound (through a therapeutic energy oragent) as is known in the art. The therapeutic energy or agent to beused includes photodynamic therapy, radiation sensitization,chemotherapy, sonodynamic therapy, and neutron bombardment. The specificdose will vary depending on the particular compound of Formula I chosen,the dosing regimen to be followed, and the particular therapeutic energyor agent with which it is administered. Such dose can be determined bymethods known in the art or as described herein.

[0183] Dosages: The specific dose will vary depending on the particularcompound of Formula I chosen, the dosing regimen to be followed, and theparticular therapeutic energy or agent with which it is administered,employing dosages within the range of about 0.01 mg/kg/treatment up toabout 100 mg/kg/treatment, preferably about 0.1 mg/kg/treatment to about50 mg/kg/treatment. It will be appreciated by one skilled in the art,however, that there are specific differences in the most effectivedosimetry depending on the apical ligands chosen, because of the widerange of properties available, such as solubilities, lipophilicityproperties, lower toxicity, and improved stability.

Administration for Photodynamic Therapy

[0184] By way of example, lutetium texaphyrin may be administered insolution, optionally in 5% mannitol USP. Dosages of about 1.0-2.0 mg/kgto about 4.0-7.0 mg/kg, preferably 3.0 mg/kg, are employed, although insome cases a maximum tolerated dose may be higher, for example about 5mg/kg. The texaphyrin is administered by intravenous injection, followedby a waiting period of from as short a time as several minutes or about3 hours to as long as about 72 or 96 hours (depending on the treatmentbeing effected) to facilitate intracellular uptake and clearance fromthe plasma and extracellular matrix prior to the administration ofphotoirradiation.

[0185] Dose levels for certain uses may range from about 0.05 mg/kg toabout 20 mg/kg administered in single or multiple doses (e.g. beforeeach fraction of radiation). The lower dosage range would be preferredfor intra-arterial injection or for impregnated stents.

[0186] The co-administration of a sedative (e.g., benzodiazapenes) andnarcotics/analgesics are sometimes recommended prior to light treatmentalong with topical administration of a local anesthetic, for exampleEmla cream (lidocaine, 2.5% and prilocaine, 2.5%) under an occlusivedressing. Other intradermal, subcutaneous and topical anesthetics mayalso be employed as necessary to reduce discomfort. Subsequenttreatments can be provided after approximately 21 days.

[0187] The optimum length of time following administration of an MTD ofFormula I until light treatment can vary depending on the mode ofadministration, the form of administration, and the type of targettissue. Typically, the MTD of Formula I persists for a period of minutesto hours, depending on the compound of Formula I, the formulation, thedose, the infusion rate, as well as the type of tissue and tissue size.

[0188] When employing photodynamic therapy, a target area is treatedwith light at about 732±16.5 nm (full width at half max) delivered by anLED device or an equivalent light source (e.g., a Quantum Device Qbeam™BMEDXM-728 Solid State Lighting System, which operates at 728 nm) at anintensity of 5-150 mW/cm² for a total light dose of 0.5-600 J/cm², or asolid state diode laser, such as the DioMed 6 WW, 15 W laser).

[0189] After the photosensitizing MTD of Formula I has beenadministered, the tissue being treated is photoirradiated at awavelength similar to the absorbance of the compound of Formula I,usually either about 400-500 nm or about 700-800 nm, more preferablyabout 450-500 nm or about 710-760 nm, or most preferably about 450-500nm or about 725-740 nm. The light source may be a laser, alight-emitting diode, or filtered light from, for example, a xenon lamp;and the light may be administered topically, endoscopically, orinterstitially (via, e.g., a fiber optic probe), or intraarterially.Preferably, the light is administered using a slit-lamp delivery system.The fluence and irradiance during the photoirradiating treatment canvary depending on type of tissue, depth of target tissue, and the amountof overlying fluid or blood. For example, a total light energy of about100 J/cm² can be delivered at a power of 200 mW to 250 mW, dependingupon the target tissue.

Administration for Chemosensitization

[0190] MTDs of Formula I may be administered before, at the same time,or after administration of one or more chemotherapeutic drugs. The MTDof Formula I may be administered as a single dose, or it may beadministered as two or more doses separated by an interval of time. TheMTD of Formula I may be administered concurrently with, or from aboutone minute to about 12 hours following, administration of achemotherapeutic drug, preferably from about 5 min to about 5 hr, morepreferably about 4 to 5 hr. The dosing protocol may be repeated, fromone to three times, for example. A time frame that has been successfulin vivo is administration of an MTD of Formula I about 5 min and about 5hr after administration of a chemotherapeutic agent, with the protocolbeing performed once per week for three weeks. Administration may beintra-arterial injection, intravenous, intraperitoneal, intramuscular,subcutaneous, oral, topical, or via a device such as a stent, forexample, with parenteral and intra-arterial administration beingpreferred, and intra-arterial being more preferred.

[0191] Administering an MTD of Formula I and a chemotherapeutic drug tothe subject may be prior to, concurrent with, or following vascularintervention. The method may begin at a time roughly accompanying avascular intervention, such as an angioplastic procedure, for example.Multiple or single treatments prior to, at the time of, or subsequent tothe procedure may be used. “Roughly accompanying a vascularintervention” refers to a time period within the ambit of the effects ofthe vascular intervention. Typically, an initial dose of an MTD ofFormula I and chemotherapeutic drug will be within 6-12 hours of thevascular intervention, preferably within 6 hours thereafter. Follow-updosages may be made at weekly, biweekly, or monthly intervals. Design ofparticular protocols depends on the individual subject, the condition ofthe subject, the design of dosage levels, and the judgment of theattending practitioner.

Administration for Radiation Sensitization

[0192] MTDs of Formula I where the metal is gadolinium are typicallyadministered in a solution containing 2 mM optionally in 5% mannitolUSP/water (sterile and non-pyrogenic solution). Dosages of 0.1 mg/kg upto as high as about 29.0 mg/kg have been delivered, preferably about 3.0to about 15.0 mg/kg (for volume of about 90 to 450 mL) may be employed,optionally with pre-medication using anti-emetics when dosing aboveabout 6.0 mg/kg. The MTD is administered via intravenous injection overabout a 5 to 10 minute period, followed by a waiting period of about 2to 5 hours to facilitate intracellular uptake and clearance from theplasma and extracellular matrix prior to the administration ofradiation.

[0193] When employing whole brain radiation therapy, a course of 30 Gyin ten (10) fractions of radiation may be administered over consecutivedays excluding weekends and holidays. In the treatment of brainmetastases, whole brain megavolt radiation therapy is delivered with ⁶⁰Co teletherapy or a ≧4 MV linear accelerator with isocenter distances ofat least 80 cm, using isocentric techniques, opposed lateral fields andexclusion of the eyes. A minimum dose rate at the midplane in the brainon the central axis is about 0.5 Gy/minute.

[0194] MTDs of Formula I used as radiation sensitizers may beadministered before, or at the same time as, or after administration ofthe ionizing radiation. The MTD of Formula I may be administered as asingle dose, as an infusion, or it may be administered as two or moredoses separated by an interval of time. Where the MTD of Formula I isadministered as two or more doses, the time interval between the MTD ofFormula I administrations may be from about one minute to a number ofdays, preferably from about 5 min to about 1 day, more preferably about4 to 5 hr. The dosing protocol may be repeated, from one to ten or moretimes, for example. Dose levels for radiation sensitization may rangefrom about 0.05 mg/kg to about 20 mg/kg administered in single ormultiple doses (e.g. before each fraction of radiation). The lowerdosage range would be preferred for intra-arterial injection or forimpregnated stents.

[0195] Administration may be intra-arterial injection, intravenous,intraperitoneal, intramuscular, subcutaneous, oral, topical, or via animpregnated or coated device such as a stent, for example, or anartery-inserted cylindrical polymer, with intravenous and intra-arterialadministration being preferred, and intra-arterial being more preferred.In one aspect of the invention, a patient having restenosis or at riskfor restenosis is administered a dose of MTD of Formula I at intervalswith each dose of radiation.

[0196] Administering a MTD of Formula I to the subject may be prior to,concurrent with, or following vascular intervention, and theintervention is followed by radiation. The method may begin prior to,such as about 24-48 hours prior to, or at a time roughly accompanyingvascular intervention, for example. Multiple or single treatments priorto, at the time of, or subsequent to the procedure may be used. “Roughlyaccompanying the vascular intervention” refers to a time period withinthe ambit of the effects of the vascular intervention. Typically, aninitial dose of MTD of Formula I and radiation will be within 1-24 hoursof the vascular intervention, preferably within about 5-24 hoursthereafter. Follow-up dosages may be made at weekly, biweekly, ormonthly intervals. Design of particular protocols depends on theindividual subject, the condition of the subject, the design of dosagelevels, and the judgment of the attending practitioner.

Administration for Sonodynamic Therapy:

[0197] The use of texaphyrins in sonodynamic therapy is described inU.S. patent application Ser. No. 09/111,148, which is incorporatedherein by reference. Texaphyrin is administered before administration ofthe ultrasound. The texaphyrin may be administered as a single dose, orit may be administered as two or more doses separated by an interval oftime. Parenteral administration is typical, including by intravenous andinterarterial injection. Other common routes of administration can alsobe employed.

[0198] Ultrasound is generated by a focused array transducer driven by apower amplifier. The transducer can vary in diameter and sphericalcurvature to allow for variation of the focus of the ultrasonic output.Commercially available therapeutic ultrasound devices may be employed inthe practice of the invention. The duration and wave frequency,including the type of wave employed may vary, and the preferred durationof treatment will vary from case to case within the judgment of thetreating physician. Both progressive wave mode patterns and standingwave patterns have been successful in producing cavitation of diseasedtissue. When using progressive waves, the second harmonic canadvantageously be superimposed onto the fundamental wave.

[0199] Preferred types of ultrasound employed in the present inventionare ultrasound of low intensity, non-thermal ultrasound, i.e.,ultrasound generated within the wavelengths of about 0.1 MHz and 5.0 MHzand at intensities between about 3.0 and 5.0 W/cm².

Administration for Neutron Capture Therapy

[0200] The use of metallotexaphyrins in neutron capture therapy isdescribed in U.S. patent application Ser. No. 60/229,366, entitled“Agents for Neutron Capture Therapy”, filed on Aug. 30, 2000, which isincorporated herein in its entirety by reference. The metallotexaphyrinis administered before administration of the neutron beam. It may beadministered as a single dose, or it may be administered as two or moredoses separated by an interval of time. Parenteral administration istypical, including by intravenous and interarterial injection. Othercommon routes of administration can also be employed.

Further Administration Protocols

[0201] MTDs of Formula I and a suitable co-therapeutic agent can also beadministered in the context of other medical procedures. For example, inallograft transplantation administration may be accomplished byperfusion of the graft prior to implantation. Following a brief periodfor uptake, e.g., by macrophages, the remaining MTD of Formula I isrinsed from the graft followed by application of the co-therapeuticagent. Administration to selectively treat diseases characterized bycirculating macrophages may be accomplished by extracorporeal contact,filtration of non-absorbed MTD of Formula I employing a lipophilicfilter, followed by application of the co-therapeutic agent.

[0202] The following examples are included to demonstrate preferredembodiments of the invention. It should be appreciated by those of skillin the art that the techniques disclosed in the examples which followrepresent techniques discovered by the inventor to function well in thepractice of the invention, and thus can be considered to constitutepreferred modes for its practice. However, those of skill in the artshould, in light of the present disclosure, appreciate that many changescan be made in the specific embodiments which are disclosed and stillobtain a like or similar result without departing from the spirit andscope of the invention.

EXAMPLES

[0203] The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

Example 1 Preparation of Compounds of Formula (I) using an AnionExchange Resin

[0204] A. Preparation of a Compound of Formula I where M is Lutetium, ALis gluconate, and n is 2

[0205] Ambersep® 900 (OH) anion exchange resin ( 100 mL, 90 meq) wasslurried in 200 mL of deionized water, poured into a Biorad® column andwashed with 500 mL of deionized water until the pH of the eluant wasapproximately 7. The resin was poured out of the column into anErlenmeyer flask and the excess solvent decanted.

[0206] 80 g of gluconic acid were dissolved in 200 mL of deionizedwater. 100 mL of the aqueous solution were added to the flask andstirred for one hour. The resultant mixture was poured onto the Bioradcolumn and the excess solution drained. The remaining 150 mL of gluconicacid solution was then passed through the column followed by 500 mL ofwater (until the pH μ4) and methanol (500 mL).

[0207] LuTex diacetate (1.1687g, 1.002 mmol) was dissolved in 50 mL ofmethanol and passed through the Biorad column. The column was washedwith 25 mL of methanol. The collected eluant was passed through thecolumn a second time and the column was washed with an additional 100 mLof methanol. The combined solutions from the column were collected andthe methanol was evaporated under reduced pressure. The green solid wasdried overnight under vacuum to afford the lutetium complex of4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis gluconate. (Alternatively, LuTex bis gluconate).Characterizing analytical data are m.w.=1438.33; g (methanol) 42200 (at733 mm), 127900 (at 475 nm); K (octanol/water) 0.011 (0.5 mg/ml), 0.028(0.05 mg/ml); pH=5.6 (H₂O); pH_((octanol/water))=5.1 (0.5 mg/ml), 5.7(0.05 mg/ml).

[0208] B. Preparation of other Compounds of Formula I where M isLutetium, and n is 2, varying AL

[0209] Similarly, following the procedure of Example IA above,substituting other ligands for gluconic acid, the following compounds ofFormula IA were prepared:

[0210] 1) Substituting glucoronic acid for gluconic acid gave thelutetium complex of:

[0211] 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethox)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis glucoronate (LuTex bis glucuronate); (0.885 mmol,98.2% yield);

[0212] 2) Substituting formic acid for gluconic acid gave the lutetiumcomplex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-pentaazapentacyclo[20.2.1.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16-18,20,22(25),23-tridecaene bis formate. (LuTex bis formate) (0.885 mmol, 98.2%yield); Characterizing analytical data are m.w. 1138.07;ε(methanol)=41700 (at 733 nm), 126400 (at 475 nm); K(octanol/water)=0.02(0.5 mg/ml), 0.02 (0.05 mg/ml); pH=5.5 (H₂O); pH(octanol/water)=5.1(0.5mg/ml), 5.6 (0.05 mg/ml).

[0213] 3) Substituting benzoic acid for gluconic acid gave the lutetiumcomplexof:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2methoxyethoxy)ethoxy]-ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosal,3,5,7,9,11(27),12,14,16,18,20,22-(25), 23-tridecaene bis benzoate.(LuTex bis benzoate) (0.885 mmol, 98.2% yield); Characterizinganalytical data are m.w.=1290.26; ε(methanol)=40600 (at 733 nm), 122800(at 475 nm); K (octanol/water)=0.34 (0.05 mg/ml); pH =6.1 (H₂O);pH_((octanol/water)-)=6.6 (0.05 mg/ml).

[0214] 4) Substituting methylvaleric acid for gluconic acid gave thelutetium complexof:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]-ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosal,3 ,5,7,9,11(27), 12,14,16,18,2, 0,22(25), 23-tridecaene bis methylvalerate (LuTex bis methylvalerate).

[0215] 5) Substituting deoxycholic acid for gluconic acid gave thelutetium complexof:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]-ethoxy]pentaaza-pentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosal,3,5,7,9,11(27),12,14,16,18,20-,22(25),23-tridecaene bis deoxycholate (LuTex bis deoxycholate). Characterizinganalytical data are m.w.=1831.2; ε(methanol)=136000; ε(4%acetate/methanol)=135000; K=2.62; pH=6.11.

[0216] 6) Similarly, substituting:

[0217] a) 3,6,9-trioxodecanoic acid;

[0218] b) 3,6-dioxoheptanoic acid;

[0219] c) methylphosphonic acid;

[0220] d) phenylphosphonic acid;

[0221] e) cholic acid; and

[0222] f) 2,5 dioxoheptanoate;

[0223] for gluconic acid, the following lutetium complexes of Formula IAwere obtained, respectively;

[0224] a) 4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1³.1⁶.1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaene bis 3,6,9-trioxodecanote;

[0225] b)4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)-ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3.6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis 3,6-dioxoheptanoate;

[0226] c)4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(1.811)0.^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaenemethylphosphonate;

[0227] d)4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14.19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene phenylphosphonate; and

[0228] e)4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis-cholate.

[0229] f)4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo[20.2.1.1³⁶.1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis 2,5 dioxoheptanoate.

[0230] C. Preparation of other Compounds of Formula I

[0231] Similarly, following the procedure of Example IA above,optionally substituting other apical ligands for gluconic acid, andoptionally substituting other metallotexaphyrins for LuTex diacetate,the following compounds of Formula IA are prepared:

[0232] gadolinium (III) complex of4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14 ,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis gluconate;

[0233] manganese (III) complex of4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1.^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22,(25),23-tridecaene bis glucuronate;

[0234] yttrium (m) complex of4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8.11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis methylvalerate;

[0235] lutetium (III) complex of4,5-dimethyl-10,23-diethyl-9,24-bis(2-hydroxyethyl)-16,17-bis[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14.19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis gluconate;

[0236] gadolinium (III) complex of4,5-dimethyl-10,23-diethyl-9,24-bis(2-hydroxyethyl)-16,17-bis[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis cholate;

[0237] lutetium (III) complex of 4-methyl-5-ethyl-10,23-diethyl-9,24-bis(2-hydroxybutyl) -16,17-bis[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaen bis formate;

[0238] calcium (II) complex of4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecae gluconate;

[0239] lutetium (III) complex of4,5-difluoro-10,23-dimethyl-9,24-bis(2-hydroxyethyl)-16,17-bis[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.1.1^(3,6).1^(8,11)0.^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25), 23-tridecaene bisgluconate;

[0240] lutetium (III) complex of4-phenyl-5-ethyl-10,23-diethyl-9,24-bis(2-hydroxyethyl)-16,17-bis[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14, 19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis gluconate;

[0241] lutetium (III) complex of4,5-dimethyl-10,23-diethyl-9,24-bis(2,3-dihydroxypropyl)-16,17-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6.1).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),bis gluconate;

[0242] lutetium (III) complex of4,5-dihydroxy-10,23-diethyl-9,24-bis(2-hydroxyethyl)-16,17-bis[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11,(27),12,14,16,18,20,22(25),23-tridecaene bis glucuronate; and

[0243] lutetium (III) complex of4,5-bis(dimethylamino)-10,23-diethyl-9,24-bis(2-hydroxyethyl)-16,17-bis[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14, 19)]heptacosa-1,3,5,7,9,11(27),12,14,16,1 8,20,22(25), 23-tridecaene bis gluconate.

Example 2

[0244] Preparation of Metallotexaphyrins via Solution Phase Extraction

[0245] The metallotexaphyrin complex (200 μmol) is dissolved in 200 mlof deionized water. 400-600 mmol of the conjugate base of the apicalligand is added, causing the precipitation of the metallotexaphyrin.Dichloromethane (200 ml) is added, and the biphasic mixture allowed tostir vigorously for several hours. The solutions are allowed to separateand the organic layer collected. The aqueous layer is extracted twicewith dichloromethane (50 ml) and the combined organics evaporated underreduced pressure and dried overnight in vacuo.

Example 3 Preparation of LuTex bis phospate via Reaction Scheme 2

[0246] 1.11 g of Lu-Tex diacetate (10 mg/ml) was dissolved in 20 mM ofphosphate (with 4% mannitol buffer) in a 150 ml beaker and stirred. Theresultant mixture was poured through a Nalgene® filter, equipped with a0.2μm Nylon® membrane to afford 10.4 mg/ml4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxypropyl)-16,17-bis[2-[2-(2methoxyethoxy)ethoxy]ethoxy]-pentaazapentacyclo[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis phospate (LuTex bis phosphate) in an acetate buffer.

Example 4 Determination of In vitro Characteristics of the Compounds ofFormula I

[0247] 4A. Extinction Coefficient

[0248] Four samples of increasing amounts of a test compound of FormulaI (between 3 mg and 11 mg) were put into separate 10 ml flasks anddissolved in methanol. Each of the solutions and one control sample(containing no test compound) were diluted to volume. The absorption at475 nm was measured by UV/V is and recorded for each of the fivesamples. The extinction coefficient for each sample was determinedaccordingly.

Extinction Coefficient (ε)=Absorption at 475 nm)(M.W. of testcompound/amount of test compound mg/volume: 100 ml

[0249] The extinction coefficient for the test compound at 475 nm wasdetermined by averaging the extinction coefficient for the four samples(not including the control). The above steps were repeated (at 733 nm)to determine the extinction coefficient for the test compound at 733 nm.When determining the extinction coefficient of aggregated test compoundsLuTex acetate, cholate or deoxycholate, the extinction coefficient at733nm is not measured. Instead, the above steps were repeatedsubstituting 4% acetic acid/methanol for methanol.

[0250] 4B. Solubility in H₂O

[0251] The test compound of Formula I was added to 10 ml of deionizedwater in increasing mass until some of the test compound was visiblyobserved not to dissolve. This mixture was then shaken, and 1.5 ml ofthe supernatant removed by a syringe equipped with a 0.22 μm filterunit. After discarding the first 1 mL of the filtrate, the remaining 0.5mL was collected and saved. 0.1 ml of the saved filtrate was added to a25 ml flask and diluted with 4% Acetic Acid/Methanol solution to volume.The absorption of the diluted solution at 475 nm was measured by UV/V isat 1, 4, and 24 hours after the solutions had been shaken as describedabove. The concentration of the compound was determined by the formula:${\lbrack{Concentration}\rbrack \quad {mg}\text{/}{ml}} = \frac{{Absorption}\quad {at}\quad 475\quad {nm} \times {Molecular}\quad {Weight}}{{Extinction}\quad {Coefficient}}$

[0252] The solubility of the test compound is determined by referencingthe concentration with the descriptive solubility term set forth in atable in U.S. Pharmacopeia The National Formulary, United StatesPharmacopeial Convention, Inc., Rockville, Md., 1997.

[0253] 4C. pH

[0254] The test compound was mixed in 5 ml of deionized water to achievea 2 mg/ml solution. The solution pH was measured using a Beckman pHmeter.

[0255] 4D. Partition Coefficient

[0256] The partition coefficient was measured using an adaptation of theprocedure outlined in Drug Stability: Principles and Practices (AAI,Inc. Wilmington, N.C. 2^(nd) Edition, 1995). A 10 ml solution of 10mg/ml of the test compound of Formula I dissolved in deionized water wasplaced in a separator funnel, to which 10 ml of 1-octanol was added. Thecombined mixture was stirred. The mixture was left to separate and theabsorption of the compound was measured in the water phase and in theoctanol phase by UV/V is at 413-417 nm (413-417 offers the closest matchin absorbance between the octanol phase and the water phase. The octanolwater partition coefficient is determined by the formula:$K = \frac{\begin{matrix}\left( {{Absorption}\quad {of}\quad {octanol}\quad {phase}\quad {at}\quad 413\text{-}417\quad {nm}} \right) \\\left( {{dilution}\quad {of}\quad {octanol}} \right)\end{matrix}}{\begin{matrix}\left( {{Absorption}\quad {of}\quad {water}\quad {phase}\quad {at}\quad 413\text{-}417\quad {nm}} \right) \\\left( {{dilution}\quad {of}\quad {water}} \right)\end{matrix}}$

[0257] The above steps were then repeated using a 10 ml sample of testcompound at 1.0 mg/ml.

[0258] 4E. Representative Compounds of The Invention

[0259] When tested in accordance with the procedures of Examples 4Athrough 4D, the characteristic data for the following representativecompounds of the invention was determined:

[0260] Lutetium Texaphyrin Diacetate, Lutetium Texaphyrin Bis-Gluconate,Lutetium Texaphyrin Bis-Formate, Lutetium Texaphyrin Bis-Benzoate,Lutetium Texaphyrin Bis-Cholate, and Lutetium TexaphyrinBis-Deoxycholate

[0261] For example, the solubility of representative compounds ofFormula I was determined in deionized water as follows (LuTex diacetateshown for comparison): Lutetium Lutetium Lutetium Lutetium LutetiumLutetium Texaphyrin Texaphyrin Texaphyrin Texaphyrin TexaphyrinTexaphyrin Bis- Bis- Bis- Bis- Bis- Diacetate Gluconate Formate BenzoateCholate Deoxycholate 2.4 mg/ml 50-80 mg/ml 2-2.5 mg/ml 0.1 mg/ml 5.0mg/ml 5.5 mg/ml

Example 5 In Vivo Studies

[0262] 5A. Biodistribution in Plaque

[0263] Plasma pK and biodistribution of the different test compounds ofFormula I in plaque are determined and compared with the plasma pK andbiodistribution in normal arterial walls. Sixteen normal male NZWrabbits, each weighing 3.5-4.0 kg are obtained from R&R Rabbitry inStanwood Oreg. Each rabbit is given an intramuscular injection ofKetamine/Rompun [(8.4 mg/kg)/(1.2 mg/kg)] and allowed to relax until theanesthetic takes effect. To induce deep anesthesia, the rabbits thenreceive a second dose of Ketamine/Rompun [(8.4mg/kg)/1.2 mg/kg)] viaintravenous injection. To expose the abdomen and back legs, each rabbitis shaved with a size 40 blade. Their eyes are coated with lubricant eyeointment (Artificial Tears).

[0264] A femoral artery cut down is performed on the right side of therabbits. Lidocaine (2%) is injected subcutaneously around the femoralartery as a local anesthetic and also applied topically to preventspasms. A No.4 French Fogarty balloon embolectomy catheter is insertedretrograde 15 cm into the abdominal aorta. The balloon is inflated with0.5-0.75 ml of hypaque contrast and pulled 3.5 cm distally toward thefemoral artery six times. The catheter is then withdrawn. The incisionline on the underlying muscle is sutured with 3-0 absorbable chromic gut(Ethicon) and the skin is sutured with 2-0 silk (Ethicon). The rabbitsare allowed to recover before being placed back into their respectivecages and are placed on a 2% cholesterol diet for 6-8 weeks.

[0265] A 3 ml blood sample is taken from each of the rabbits and thecholesterol level for each sample is determined and recorded. Fourteenof the sixteen rabbits are injected with 10 mg/kg of one of the testcompounds. One of the remaining rabbits is a pure control and receivesneither test compound nor buffer. The other remaining rabbit receives notest compound but does receive 5% mannitol buffer. A 3 ml blood sampleis drawn from each of the rabbits at 1, 5 and 24 hours post injection.Each 3ml blood sample is handled with minimum exposure to ambient lightand spun for 10 minutes in a centrifuge at 2,000 rpm within 30 minutesof the blood draw. The supernatant (plasma) is removed by a pipette andput into a 1.8ml cryotube. The plasma is frozen at −70° C. for futureanalysis (see part B of this example). All of the rabbits are sacrificed24 hours after injection.

[0266] At necropsy, the heart and aorta, including the iliac arteries,are harvested in a minimum amount of ambient light. The length of theplaque (cm) in the aorta is measured. The iliac arteries and lowerabdominal aortic sections of the above rabbits were subjected tofluorescence spectral bioimaging. Each aorta is excised, cutlongitudinally to expose the luminal surface and washed thoroughly withisotonic saline. The luminal surfaces of the iliac arteries and thelower abdominal aorta were compared to the surrounding visually normalaortic surfaces. The aortic samples were illuminated with a Cogent Lightillumination system equipped with a coaxial LightWear headlight (CogentLight Technologies, Inc., Santa Clara, Calif.) and a 470 nm interferencefilter (10 nm bandwidth, Oriel Corporation, Stratford, Conn.). Imageswere collected with the SD200 spectral bio-imaging system (AppliedSpectral Imaging, Carlsbad, Calif.). A 715 nm long pass filter isutilized (Oriel Corporation, Stratford, Conn.) with a fluorescenceemission range of 650-850 nm being captured. Each signal is averagedover 5 pixels. Each acquired measurement is imaged with a CCD cameracoupled to an interferometer, and then the signal Fourier transformedallowing spectral identification at every pixel as described by Gariniet al., Spectral Bioimaging, John Wiley and Sons, Inc. New York. 1996;87-124). The results of the fluorescence signal measurements in plaquevs. normal tissue are plotted.

[0267] 5B. Plasma Concentration

[0268] The clearance rate of the test compound is also particularlyimportant to measure. Plasma samples from each of the test compounds(see part A of this example) are mixed with 10 mM Triton X-100 and thefluorescence optimum is measured at 745 nm by scanning between 700-800nm using a 450 nm excitation. A standard curve is run to insure that thefluorescence of the samples lies on the linear portion of the curve. Theentire fluorescence emission spectrum is observed by using both amonochromator and CCD array. This permits differentiating between thepeak at 745 nm and any possible extraneous fluorescence that might havea different optimum, and tail off into the 745 nm region. Test compoundaccumulation is expressed as μg drug/g tissue (wet weight) or μg/ml inplasma.

Results

[0269] Plasma Concentration in μg/ml 1 Hour 5 Hours 24 Hours 2 mg/mlbisformate 3.9 0.5 0.3 2 mg/ml bisgluconate 5.6 1.5 0.4 10 mg/mlbisgluconate 2.4 0.7 0.3 10 mg/ml bisacetate 4.5 0.8 0.3 2 mg/mlbisacetate 2.1 0.3 0.2

[0270] The numbers of rabbits that are treated with each test compoundin parts A and B of this example are set forth in the table below.Number of Rabbits Test compound Injected None (control) 1 20 ml of 5%mannitol 1 20 ml of LuTex diacetate in 2 g of 5% mannitol 3 20 ml ofLuTex bis-gluconate in 2 g of 5% mannitol 3 2 ml of LuTex bis-gluconatein 100 mg of 5% mannitol 3 2 ml of LuTex diacetate in 100 mg? of_%phosphate buffer 3 20 ml of LuTex bis-formate in 2 g of 5% mannitol 2

[0271] 5C. Efficacy Analysis

[0272] The test compounds are compared for efficacy as phototherapeuticagents in cancer. In order to evaluate the effectiveness and determinethe optimal drug and light regiment of the various test compounds, eachof the test compounds is used as a photodynamic (PDT) agent using themurine EMT6 sarcoma model. The EMT6 tumor cell line, murine mammarysarcoma, (Stanford University, Stanford, Calif.) is maintained throughin vivo/in vitro propagation according to the established procedure ofRockwell and Kallman, found in, “Growth and cell Population Kinetics ofSingle and Multiple KHT Sarcomas” Cell Tissue Kinetics, 1972, 1,pp.449-457. The EMT6 cells (1×10⁶) are grown in 50 μl Waymouth's Medium(MB752/1, GIBCO, Grand Island N.Y.), supplemented with 15% fetal bovineserum (GIBCO, Grand Island N.Y.) and penicillin/streptomycin (Sigma, St.Louis, Mo.). Thirty Two female Balb/c mice weighing 18-22 g and between10 to 12 weeks old, are obtained from Simonsen Laboratories, GilroyCalif. The right flanks of the mice are shaved and depiled the day priorto tumor inoculation. The tumor cells (1×10⁶ in 0.05 ml Waymouth'sMedium) are injected subcutaneously into the right flanks of therecipient mice. The length (1), width (w), and height (h) of the tumorare measured 3 times a week with a vernier caliper. Tumor volume iscalculated assuming the conformation of a hemiellipsoid, and followingthe formula:

V=π/6×(1)×(w)×(h)

[0273] Mice are entered into PDT studies when their tumors reachedsurface diameters of between 5-7 mm and depths of 3-5 mm. The tumors aremeasured for 40 days post PDT treatment. Each test compound (10 mg/kg)is administered to eight mice by tail-vein injection, and the tumor isirradiated 5 hours later by localized laser irradiation using a ALGaAsdiode laser (Diomed Cambridge, UK) at 732 mm. Eight mice used ascontrols are injected with 10 mg/kg of 5% mannitol but no test compound,and are also irradiated 5 hours post injection by localized laserirradiation at 732 mm. During the laser irradiation, each mouse isrestrained with laboratory tape. A 400 μm diameter fiberoptic cablecouples the laser to the microlens which produces uniform lightintensity in the treatment field. The light fluences are 100 J/cm², andthe power density is set to 75 mW/cm². Power measurements are made witha power meter (Scientech Boulder, Co).

[0274] When each mouse appears moribund or when the tumor appears togrow to four times the prestudy volume, it is removed from the study. Asillustrated in FIG. 3, the number of mice remaining in the study(percent survival) is plotted against the number of days aftertreatment. The mice are euthanized by either carbon dioxide or methaneinhalation.

[0275] The different test compounds, number of mice treated andtreatment regiments are outlined below. Number of Test compound MiceTreated Treatment 20 ml of 5% mannitol 8 75 m W/cm² @ 100 J/cm²(control) 20 ml of LuTex diacetate (2 8 75 m W/cm² @ 100 J/cm² mg/ml in5% mannitol) 20 ml of LuTex bis-gluconate 8 75 m W/cm² @ 100 J/cm² (2mg/ml in 5% mannitol) 20 ml of LuTex bis-formate 8 75 m W/cm² @ 100J/cm² (2 mg/ml in 5% mannitol)

[0276] The following examples illustrate the preparation ofrepresentative pharmaceutical formulations containing a compound ofFormula I, such as those prepared in accordance with Example 1.

Example 6

[0277] Hard gelatin capsules containing the following ingredients areprepared: Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch305.0 Magnesium stearate 5.0

[0278] The above ingredients are mixed and filled into hard gelatincapsules in 340 mg quantities.

Example 7

[0279] A tablet formula is prepared using the ingredients below:Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

[0280] The components are blended and compressed to form tablets, eachweighing 240 mg.

Example 8

[0281] A dry powder inhaler formulation is prepared containing thefollowing components: Ingredient Weight % Active Ingredient 5 Lactose 95

[0282] The active ingredient is mixed with the lactose and the mixtureis added to a dry powder inhaling appliance.

Example 9

[0283] Tablets, each containing 30 mg of active ingredient, are preparedas follows: Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mgStarch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10% solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate  0.5 mg Talc  1.0 mg Total 120 mg

[0284] The active ingredient, starch and cellulose are passed through aNo. 20 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Example 10

[0285] Capsules, each containing 40 mg of medicament are made asfollows: Quantity Ingredient (mg/capsule) Active Ingredient  40.0 mgStarch 109.0 mg Magnesium stearate  1.0 mg Total 150.0 mg

[0286] The active ingredient, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

Example 1

[0287] Suppositories, each containing 25 mg of active ingredient aremade as follows: Ingredient Amount Active Ingredient   25 mg Saturatedfatty acid glycerides to 2,000 mg

[0288] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Example 12

[0289] Suspensions, each containing 50 mg of active ingredient per 5.0mL dose are made as follows: Ingredient Amount Active Ingredient 50.0 mgXanthan gum  4.0 mg Sodium carboxymethyl cellulose (11%)Microcrystalline cellulose (89%) 50.0 mg Sucrose  1.75 g Sodium benzoate10.0 mg Flavor and Color q.v. Purified water to  5.0 mL

[0290] The active ingredient, sucrose and xanthan gum are blended,passed through a No. 10 mesh U.S. sieve, and then mixed with apreviously made solution of the microcrystalline cellulose and sodiumcarboxymethyl cellulose in water. The sodium benzoate, flavor, and colorare diluted with some of the water and added with stirring. Sufficientwater is then added to produce the required volume.

Example 13

[0291] A subcutaneous formulation may be prepared as follows: IngredientQuantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

[0292] Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system used for the transport ofbiological factors to specific anatomical regions of the body isdescribed in U.S. Pat. No. 5,011,472 , which is herein incorporated byreference.

[0293] Indirect techniques, which are generally preferred, usuallyinvolve formulating the compositions to provide for drug latentiation bythe conversion of hydrophilic drugs into lipid-soluble drugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drug torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barrier. Alternatively, the delivery of hydrophilicdrugs may be enhanced by intra-arterial infusion of hypertonic solutionswhich can transiently open the blood-brain barrier.

Example 14

[0294] An injectable preparation is prepared having the followingcomposition: Ingredients Amount Lu-Tex bis-gluconate 2.0 mg/ml Mannitol,USP  50 mg/ml Gluconic acid, USP q.s. (pH 5-6) water (distilled,sterile) q.s. to 1.0 ml Nitrogen Gas, NF q.s.

[0295] Other compounds of Formula I, such as those prepared inaccordance with Example 1, can be used as the active compound in thepreparation of the injectable formulations of this example.

Example 15

[0296] A topical preparation is prepared having the followingcomposition: Ingredients grams Lu Tex bis benzoate 0.2-10 Span 60 2.0 Tween 60 2.0  Mineral oil 5.0  Petrolatum 0.10 Methyl paraben 0.15Propyl paraben 0.05 BHA (butylated hydroxy anisole) 0.01 Water q.s. to100

[0297] All of the above ingredients, except water, are combined andheated to 60° C. with stirring. A sufficient quantity of water at 60° C.is then added with vigorous stirring to emulsify the ingredients, andwater then added q.s. 100 g.

[0298] Other compounds of Formula I, such as those prepared inaccordance with Example 1, can be used as the active compound in thepreparation of the topical formulations of this example

[0299] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto. All of the above references are hereinincorporated by reference in their entirety to the same extent as ifeach individual reference was specifically and individually indicated tobe incorporated by reference in its entirety.

What is claimed is:
 1. A compound of the Formula:

 wherein: M is a monovalent, divalent, trivalent, or tetravalent metalcation; AL is an apical ligand; with the proviso that AL is not derivedfrom acetic acid, nitric acid, or hydrochloric acid; n is 1 when M is adivalent cation, or n is 2 when M is a trivalent cation; R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, and R⁹, are independently chosen from the groupconsisting of hydrogen, halogen, hydroxyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted haloalkyl; alkylalkoxy, nitro, acyl, optionallysubstituted alkoxy, saccharide, optionally substituted amino, carboxyl,optionally substituted carboxyalkyl, optionally substitutedcarboxyamide, optionally substituted carboxyamidealkyl, optionallysubstituted heterocycle, optionally substituted cycloalkyl, optionallysubstituted arylalkyl, optionally substituted heteroarylalkyl,optionally substituted heterocycloalkylalkyl; and a group-X-Y, in whichX is a covalent bond or a linker and Y is a catalytic group, achemotherapeutic agent, or a site-directing molecule, and; R⁵, R¹⁰, R¹¹,and R¹² are independently hydrogen, optionally substituted alkyl,optionally substituted aryl, optionally substituted alkoxy, optionallysubstituted carboxyalkyl, or optionally substituted carboxyamidealkyl;with the proviso that the halogen is other than iodide and the haloalkylis other than iodoalkyl.
 2. The compound of claim 1, wherein M is adivalent metal cation chosen from Ca(II), Mn(II), Co(II), Ni(II),Zn(II), Cd(II), Hg(II), Fe(II), Sm(II), and UO₂(II), or a trivalentmetal cation chosen from Mn(III), Co(III), Ni(III), Fe(III), Ho(III),Ce(III), Y(III), In(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III),Tb(III), Dy(III), Er(III),Tm(III), Yb (III), Lu(III), La(III), andU(III).
 3. The compound of claim 2, wherein the apical ligand is derivedfrom the group consisting of gluconic acid, glucoronic acid, cholicacid, deoxycholic acid, methylphosphonic acid, phenylphosphonic acid,phosphoric acid, formic acid, propionic acid, butyric acid, pentanoicacid, 3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic acid,2,5-dioxoheptanoic acid, methylvaleric acid, glycolic acid, pyruvicacid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid,fumaric acid, tartaric acid, citric acid, methanesulfonic acid,ethanesulfonic acid, benzoic acid, salicylic acid, 3-fluorobenzoic acid,4-aminobenzoic acid, cinnamic acid, mandelic acid, andp-toluene-sulfonic acid.
 4. The compound of claim 3, wherein: R¹R², R³,and R⁴ are optionally substituted alkyl of 1-10 carbon atoms, R⁵, R⁶,R⁹, R¹⁰, R¹¹ and R¹² are hydrogen or alkyl of 1-6 carbon atoms; and R⁷and R⁸ are optionally substituted alkoxy or alkylalkoxy.
 5. The compoundof claim 4, wherein R¹ at each occurrence is hydroxyalkyl, R⁴ at eachoccurrence is alkyl, and R⁵, R⁶, R⁹, R¹⁰, R¹¹and R¹² are hydrogen. 6.The compound of claim 5, wherein R¹ at each occurrence is 2-hydroxyethylor 3-hydroxypropyl, R⁴ at each occurrence is methyl or ethyl, and R⁷ andR⁸ are both —O(CH₂CH2O)_(x)Z, where x is an integer of 2-5, and Z ishydroxy or alkyl of 1-6 carbon atoms.
 7. The compound of claim 6,wherein Z is methyl or hydroxy and x is 1-3.
 8. The compound of claim 7,wherein M is Lu(III) or or Gd(III) and AL is derived from gluconic acid,glucoronic acid, cholic acid, deoxycholic acid, methylphosphonic acid,phenylphosphonic acid, phosphoric acid, formic acid, benzoic acid,methylvaleric acid, 3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic acid,or 2,5-dioxoheptanoic acid.
 9. The compound of claim 8, wherein R¹ is3-hydroxypropyl, R² and R³ are ethyl, R⁴ is methyl, and R⁷ and R⁸ are2-[2-[-(2-methoxyethoxy)ethoxy]ethoxy.
 10. The compound of claim 9,wherein M is Lu(III) and the apical ligand is derived from gluconicacid, namely the lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxy propyl)-16,17-bis[2-[2-(2methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis gluconate.
 11. A method for treating a disease orcondition in a mammal resulting from the presence of neoplastic tissue,neovascularization, or an atheroma, which method comprises: a)administering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of claim 1, and b) treating the area inproximity to the neoplastic tissue with a therapeutic energy means orwith a chemotherapeutic agent; or c) treating the area in proximity tothe neovascularization or atheroma with a therapeutic energy means. 12.The method of claim 11, wherein the therapeutic energy means is chosenfrom photoirradiation, ionizing radiation, neutron irradiation, andultrasound.
 13. The method of claim 12, wherein M is a divalent metalcation chosen from Ca(II), Mn(II), Co(II), Ni(II), Zn(II), Cd(II),Hg(II), Fe(II), Sm(II), and UO₂(II), or a trivalent metal cation chosenfrom Mn(III), Co(III), Ni(Ill), Fe(III), Ho(III), Ce(III), Y(III),In(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III),Er(III), Tm(III), Yb(III), Lu(III), La(III), and U(III).
 14. The methodof claim 13, wherein the apical ligand is derived from the groupconsisting of gluconic acid, glucoronic acid, cholic acid, deoxycholicacid, methylphosphonic acid, phenylphosphonic acid, phosphoric acid,formic acid, propionic acid, butyric acid, pentanoic acid,3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic acid, 2,5-dioxoheptanoicacid, methylvaleric acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid,benzoic acid, salicylic acid, 3-fluorobenzoic acid, 4-aminobenzoic acid,cinnamic acid, mandelic acid, and p-toluene-sulfonic acid.
 15. Themethod of claim 14, wherein: R¹ R², R³, and R⁴are optionally substitutedalkyl of 1-10 carbon atoms, R⁵, R⁶, R⁹, R¹⁰, R¹¹ and R¹² are hydrogen oralkyl of 1-6 carbon atoms; and R⁷ and R⁸ are optionally substitutedalkoxy or alkylalkoxy.
 16. The method of claim 15, wherein R¹ at eachoccurrence is hydroxyalkyl, R⁴ at each occurrence is alkyl, and R⁵, R⁶,R⁹, R¹⁰, R¹¹ and R¹² are hydrogen.
 17. The method of claim 16, whereinR¹ at each occurrence is 2-hydroxyethyl or 3-hydroxypropyl, R⁴ at eachoccurrence is methyl or ethyl, and R⁷ and R⁸ are both —O(CH₂CH₂O)_(x)Z,where x is an integer of 2-5, and Z is hydroxy or alkyl of 1-6 carbonatoms.
 18. The method of claim 17, wherein Z is methyl or hydroxy and xis 1-3.
 19. The method of claim 18, wherein M is Lu(III) or or Gd(III)and AL is derived from gluconic acid, glucoronic acid, cholic acid,deoxycholic acid, methylphosphonic acid, phenylphosphonic acid,phosphoric acid, formic acid, benzoic acid, methylvaleric acid,3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic acid, or2,5-dioxoheptanoic acid.
 20. The method of claim 19, wherein R¹ is3-hydroxypropyl, R² and R³ are ethyl, R⁴ is methyl, and R⁷ and R⁸ are2-[2-[-(2-methoxyethoxy)ethoxy]ethoxy.
 21. The method of claim 20,wherein M is Lu(III) and the apical ligand is derived from gluconicacid, namely the lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxy propyl)-16,17-bis[2- [2-(2methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis gluconate.
 22. A pharmaceutical composition comprisingat least one pharmaceutically acceptable excipient and a therapeuticallyeffective amount of a compound of claim
 1. 23. The composition of claim22, wherein M is a divalent metal cation chosen from Ca(II), Mn(II),Co(II), Ni(II), Zn(II), Cd(II), Hg(II), Fe(II), Sm(II), and UO₂(II), ora trivalent metal cation chosen from Mn(III), Co(III), Ni(III), Fe(III),Ho(III), Ce(III), Y(III), In(II), Pr(III), Nd(III), Sm(III), Eu(III),Gd(III), Tb(III), Dy(III), Er(III), Tm(III), Yb(III), Lu(III), La(III),and U(III).
 24. The composition of claim 23, wherein the apical ligandis derived from the group consisting of gluconic acid, glucoronic acid,cholic acid, deoxycholic acid, methylphosphonic acid, phenylphosphonicacid, phosphoric acid, formic acid, propionic acid, butyric acid,pentanoic acid, 3,6,9-trioxodecanoic acid, 3,6-dioxoheptanoic acid,2,5-dioxoheptanoic acid, methylvaleric acid, glycolic acid, pyruvicacid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid,fumaric acid, tartaric acid, citric acid, methanesulfonic acid,ethanesulfonic acid, benzoic acid, salicylic acid, 3-fluorobenzoic acid,4-aminobenzoic acid, cinnamic acid, mandelic acid, andp-toluene-sulfonic acid.
 25. The composition of claim 24, wherein: R¹R², R³, and R⁴ are optionally substituted alkyl of 1-10 carbon atoms,R⁵, R⁶, R⁹, R¹⁰, R¹¹ and R¹² are hydrogen or alkyl of 1-6 carbon atoms;and R⁷ and R⁸ are optionally substituted alkoxy or alkylalkoxy.
 26. Thecomposition of claim 25, wherein R¹ at each occurrence is hydroxyalkyl,R⁴ at each occurrence is alkyl, and R⁵, R⁶, R⁹, R¹⁰, R¹¹ and R¹² arehydrogen.
 27. The composition of claim 26, wherein R¹ at each occurrenceis 2-hydroxyethyl or 3-hydroxypropyl, R⁴ at each occurrence is methyl orethyl, and R⁷ and R⁸ are both —O(CH₂CH₂O)_(x)Z, where x is an integer of2-5, and Z is hydroxy or alkyl of 1-6 carbon atoms.
 28. The compositionof claim 27, wherein Z is methyl or hydroxy and x is 1-3.
 29. Thecomposition of claim 28, wherein M is Lu(III) or or Gd(III) and AL isderived from gluconic acid, glucoronic acid, cholic acid, deoxycholicacid, methylphosphonic acid, phenylphosphonic acid, phosphoric acid,formic acid, benzoic acid, methylvaleric acid, 3,6,9-trioxodecanoicacid, 3,6-dioxoheptanoic acid, or 2,5-dioxoheptanoic acid.
 30. Thecomposition of claim 29, wherein R¹ is 3-hydroxypropyl, R² and R³ areethyl, R⁴ is methyl, and R⁷ and R⁸ are2-[2-[-(2-methoxyethoxy)ethoxy]ethoxy.
 31. The composition of claim 30,wherein M is Lu(III) and the apical ligand is derived from gluconicacid, namely the lutetium (III) complex of:4,5-diethyl-10,23-dimethyl-9,24-bis(3-hydroxy propyl)-16,17-bis[2-[2-(2methoxyethoxy)ethoxy]ethoxy]pentaazapentacyclo-[20.2.1.1^(3,6).1^(8,11).0^(14,19)]heptacosa-1,3,5,7,9,11(27),12,14,16,18,20,22(25),23-tridecaene bis gluconate.
 32. A process for preparing ametallotexaphyrin having the formula: (T-M)^(n+)(AL ⁻)_(n)  wherein: Tis a texaphyrin; M is a divalent or trivalent metal cation constrainedwithin the binding cavity of the texaphyrin; AL is an apical ligand; andn is an integer of 1-5; comprising: a) contacting an apical ligand (AL)Hwith a quartenary amine resin; b) contacting the resin complex producedin step a) with a metallotexaphyrin of the formula: (T-M)^(n+)(AL ₁⁻)_(n) in which T and M are as defined above; (AL₁) represents adisplaceable apical ligand; and n is an integer of 1-5.
 33. The processof claim 32, wherein M is Lu(III) or Gd(III), (AL₁) is acetate, and n is2.
 34. The process of claim 33, wherein (AL)H is chosen from formicacid, propionic acid, butyric acid, pentanoic acid, 3,6,9-trioxodecanoicacid, 3,6-dioxoheptanoic acid, 2,5-dioxoheptanoic acid, methylvalericacid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonicacid, succinic acid, maleic acid, fumaric acid, tartaric acid, citricacid, methanesulfonic acid, ethanesulfonic acid, benzoic acid, salicylicacid, 3-fluorobenzoic acid, 4-aminobenzoic acid, cinnamic acid, mandelicacid, and p-toluene-sulfonic acid.
 35. A process for preparing ametallotexaphyrin having the formula: (T-M)^(n+)(AL ⁻)_(n)  wherein: Tis a texaphyrin; M is a divalent or trivalent metal cation constrainedwithin the binding cavity of the texaphyrin; AL is an apical ligand; andn is an integer of 1-5; comprising: contacting a metallotexaphyrin ofthe formula: (T-M)^(n+)(AL₁ ⁻)_(n) in which T and M are as definedabove; (AL₁) represents a displaceable apical ligand; and n is aninteger of 1-5; with an excess of an apical ligand (AL)H; at atemperature of 20-100° C.
 36. The process of claim 35, wherein M isLu(III) or Gd(III), (AL₁) is acetate, and n is
 2. 37. The process ofclaim 36, wherein (AL)H is chosen from formic acid, propionic acid,butyric acid, pentanoic acid, 3,6,9-trioxodecanoic acid,3,6-dioxoheptanoic acid, 2,5-dioxoheptanoic acid, methylvaleric acid,glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, benzoic acid, salicylic acid,3-fluorobenzoic acid, 4-aminobenzoic acid, cinnamic acid, mandelic acid,and p-toluene-sulfonic acid.